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p53
P53 p53(3)

p53, the guardian of the genome, as a tumor suppressor and transcription factor, located on chromosome 17.(1) p53 becomes activated in response to DNA damage, oxidative stress, osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events: (1) the half-life of the p53 protein is increased, leading to a quick accumulation of p53 in stressed cells, and (2) a conformational change activates p53 as a transcription regulator in these cells. Following DNA damage, p53 levels rise, and proliferating cells arrest in G1. This arrest is mediated by stimulation of expression of p21CIP1, the cyclin kinase inhibitor.(2, 3)
P53 has seven domains:
1. an acidic N-terminus transcription-activation domain (TAD),
2. an activation domain 2 important for apoptotic activity,
3. a proline rich domain important for the apoptotic activity,
4. a central DNA-binding core domain (DBD), responsible for binding the p53 co-repressor LMO3,
5. a nuclear localization signaling domain,
6. a homo-oligomerization domain, and
7. a C-terminal involved in downregulation of DNA binding of the central domain.(4)
The activation of p53 is caused by the phosphorylation of its N-terminal domain.(3) The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups: (1) protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, and p38 MAPK), and (2) protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, and TP53RK) implicated in the genome integrity checkpoint.(3) Mdm2 or HDM2, a product of p53, binds to p53, preventing its action in unstressed cells.(3) Mutant p53 proteins often do not induce MDM2, and are thus able to accumulate at very high concentrations.(3, 5) Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. Ubiquitylation of p53 is reversible. A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. Pin1 induces a conformational change in p53, which prevents Mdm2-binding. Phosphorylation also allows for binding of transcriptional co-activators, like p300and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.(3) p53 interacts with: BAK1, BRCA1, BRCA2, Cdk1, CDK7, HSP90AA1, HIF1A, MAPK9, NF-?B, PARP1, PLK3, PTEN, and STAT3.(3, 6, 7) Activated p53 binds DNA and activates microRNA miR-34a, WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes.(3)
The p53 tumor suppressor protein is able to mediate permanent cell cycle arrest (senescence) as well as apoptosis, meaning that its reintroduction into proliferating cancer cells may lead to irreversible growth arrest or tumor cell killing.(8, 9) In its anti-cancer role, p53 works through several mechanisms:
1. activate DNA repair proteins when DNA has sustained damage.
2. arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition.
3. initiate apoptosis - programmed cell death - if DNA damage proves to be irreparable.
More than 50% of human tumors contain a mutation or deletion of P53.(10) Most P53 cancer mutations destroy the ability of the protein to bind to its target DNA sequences. Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity. Oncogenes also stimulate p53 activation, mediated by the proteinp14ARF.(3)

Drugs/Indications
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
rAd-p53 Gendicine Shenzhen SiBiono GeneTech Mkt (China): HNN; P3: thyroid; P2: NSCLC trials
cenersen EL625 Aezea Eleos P2: NHL, CLL, AML, lymphoma; P1: MDS trials
quinacrine, mepacrine Atabrine Incuron, noncorporate P2: CRC, RCC (withdrawn), PC; P1/2: NSCLC trials
APR-246 Aprea AB P1/2: ovarian; P1: solid, PC, hem trials
thioureidobutyronitrile Kevetrin Cellceutix P1: solid trials
CBL0137 Cleveland P1: solid trials
CGM097 Novartis P1: solid trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
INGN 225 Introgen Last new trial started in 2007; P2: SCLC trials
TNP-470 terminated; P2: pancreatic; P1: sarcoma, Kaposi's trials
Ad5CMV-p53 gene INGN 201 Advexin Introgen Failed FDA 2008; Last trial started in 2003; P2: BC, HNN; P1: bladder, ovarian, peritoneal, HCC, lung, brain, CNS trials
p53 peptide vaccine noncorporate Last trial started in 2008; P2: lung, ovarian; P1: HNN, BC, CRC, pancreatic, sarcoma trials
News
References

1. Delgado MD1 LJ. Gene expression regulation and cancer. Clin Transl Oncol. 2006;8(11):780-7.

2. Isobe M, Emanuel B, Givol D, Oren M, Croce C. Localization of gene for human p53 tumour antigen to band 17p13. 1986.

3. P53. [cited]; Available from: http://en.wikipedia.org/wiki/P53.

4. Harms KL, Chen X. The C terminus of p53 family proteins is a cell fate determinant. Molecular and cellular biology. 2005;25(5):2014-30.

5. Bullock AN, Henckel J, DeDecker BS, Johnson CM, Nikolova PV, Proctor MR, et al. Thermodynamic stability of wild-type and mutant p53 core domain. Proceedings of the National Academy of Sciences. 1997;94(26):14338-42.

6. An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM. Stabilization of wild-type p53 by hypoxia-inducible factor 1?. Nature. 1998;392(6674):405-8.

7. Bahassi EM, Conn CW, Myer DL, Hennigan RF, McGowan CH, Sanchez Y, et al. Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways. Oncogene. 2002;21(43):6633-40.

8. Galluzzi L, Morselli E, Kepp O, Tajeddine N, Kroemer G. Targeting p53 to mitochondria for cancer therapy. Cell Cycle. 2008;7(13):1949-55.

9. Vousden KH. Outcomes of p53 activation-spoilt for choice. Journal of Cell Science. 2006;119(24):5015-20.

10. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253(5015):49-53.



News
Tuesday, September 20, 2016 9:46 AM|Cox, A. G., Tsomides, A., Kim, A. J., Saunders, D., Hwang, K. L., Evason, K. J., Heidel, J., Brown, K. K., Yuan, M., Lien, E. C., Lee, B. C., Nissim, S., Dickinson, B., Chhangawala, S., Chang, C. J., Asara, J. M., Houvras, Y., Gladyshev, V. N., Goessling, W.|Proceedings of the National Academy of Sciences current issue|Labels: P53
Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling...
Friday, September 16, 2016 4:27 PM|Kaiyu Liu, Bo Jin, Chenglin Wu, Jianming Yang, Xiangwen Zhan, Le Wang, Xiaomeng Shen, Jing Chen, Hao Chen, Zebin Mao|International Journal of Biological Sciences|Labels: P53

Cellular senescence is a state of permanent cellular arrest that provides an initial barrier to cell transformation and tumorigenesis. In this study, we report that expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), a cytoplasmic 2-electron reductase, is induced during oncogene-induced senescence (OIS). Depletion of NQO1 resulted in the delayed onset of senescence. In contrast, ectopic expression of NQO1 enhanced the senescence phenotype. Analysis of the mechanism underlying the up-regulation of NQO1 expression during senescence identified that NQO1 promotes p53 accumulation in an MDM2 and ubiquitin independent manner, which reinforces the cellular senescence phenotype. Specifically, we demonstrated that NRF2/KEAP1 signaling regulates NQO1 expression during OIS. More importantly, we confirmed that depletion of NQO1 facilitates cell transformation and tumorigenesis, which indicates that NQO1 takes part in the senescence barrier and has anti-oncogenic properties in cell transformation.

Friday, September 16, 2016 11:13 AM|Zhong, Y., Macgregor-Das, A. M., Saunders, T., Whittle, M., Makohon-Moore, A., Kohutek, Z., Poling, J., Herbst, B., Javier, B., Cope, L., Leach, S. D., Hingorani, S. R., Iacobuzio-Donahue, C. A.|Clinical Cancer Research Online First Articles|Labels: P53, pancreatic cancer

Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored. Experimental Design: KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated and the frequency and morphology of organ-specific hematogenous metastases compared to that seen in KPTC and KTC littermates (Tgfbr2+/-). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases. Results: The frequency of hematogenous metastasis in KPTC mice was significantly lower than for KPC mice (41% vs 68%, p<0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases whereas liver metastases in KPTC mice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses of KPC cells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases suggesting the ability to colonize is in part developed within the primary site, a phenomenon we refer to as the "Cinderella effect". Conclusions: These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically.

Friday, September 16, 2016 10:23 AM|Weihua Yu, Xiaodi Zhang, Jiangzheng Liu, Xin Wang, Shuang Li, Rui Liu, Nai Liao, Tao Zhang, Chunxu Hai|International Journal of Biological Sciences|Labels: electron transport, P53, liver cancer

P53 is known as a transcription factor to control apoptotic cell death through regulating a series of target genes in nucleus. There is accumulating evidences show that p53 can directly induce cell apoptosis through transcription independent way at mitochondria. However, the mechanism by which p53 translocation into mitochondria in response to oxidative stress remains unclear. Here, glucose oxidase (GOX) was used to induce ROS generation in HepG2 cells and liver tissues of mice. The results showed that p53 was stabilized and translocated to mitochondria in a time and dose dependent manner after GOX exposure. Interestingly, as an inhibitor of mitochondrial permeability transition, cyclosporine A (CsA) was able to effectively reduce GOX mediated mitochondrial p53 distribution without influencing on the expression of p53 target genes including Bcl-2 and Bax. These indicated that CsA could just block p53 entering into mitochondria, but not affect p53-dependent transcription. Meanwhile, CsA failed to inhibit the ROS generation induced by GOX, which indicated that CsA had no antioxidant function. Moreover, GOX induced typical apoptosis characteristics including, mitochondrial dysfunction, accumulation of Bax and release of cytochrome C in mitochondria, accompanied with activation of caspase-9 and caspase-3. These processions were suppressed after pretreatment with CsA and pifithrin-μ (PFT-μ, a specific inhibitor of p53 mitochondrial translocation). In vivo, CsA was able to attenuate p53 mitochondrial distribution and protect mice liver against from GOX mediated apoptotic cell death. Taken together, these suggested that CsA could suppress ROS-mediated p53 mitochondrial distribution and cell apoptosis depended on its inhibition effect to mitochondrial permeability transition. It might be used to rescue the hepatic cell apoptosis in the patients with acute liver injury.

Thursday, September 15, 2016 3:30 PM|Nicholas F. Lawrence, Marc R. Hammond, Dennie T. Frederick, Yuhua Su, Dora Dias-Santagata, April Deng, M. Angelica Selim, Meera Mahalingam, Keith T. Flaherty, Mai P. Hoang|Journal of the American Academy of Dermatology|Labels: P53, melanoma
The prognostic role Ki-67, p53, and p16 immunostains and RET (rearranged during transfection) polymorphism in desmoplastic melanoma has not been evaluated.
Thursday, September 15, 2016 12:40 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: P53, PI3K, CLL
Despite impressive therapeutic progress represented by the advent of chemoimmunotherapy, chronic lymphocytic leukemia (CLL) remains incurable by conventional modalities. Refractory CLL defined by non-response to treatment or relapse/progression within 6 months is associated with multiple unfavourable prognostic factors such as p53 pathway disruption, deteriorating patient condition, increased risk of severe infections, and poor response to treatment, resulting in a very short overall survival. Therefore, refractory CLL represents a highly challenging situation for the hematologist as well as the patient. The amount and quality of data on refractory CLL are rather limited as clinical trials usually combine patients with relapsed and refractory disease. Therapeutic options for refractory CLL include alemtuzumab, ofatumumab, fludarabine- and bendamustine-based regimens, platinum-based aggressive protocols and high-dose corticosteroids combined with monoclonal antibodies. The recent introduction of ibrutinib and idelalisib, small molecules interfering with B-cell receptor pathways, revolutionized the treatment of refractory CLL by the novel concept of long-term, oral treatment leading to impressive progression-free and overall survival improvement. Allogeneic stem cell transplantation is still considered the only option with curative potential. This review focuses on the currently available therapeutic strategies for refractory CLL.
Thursday, September 15, 2016 6:45 AM|Althubiti, M., Rada, M., Samuel, J., Escorsa, J. M., Najeeb, H., Lee, K.-G., Lam, K.-P., Jones, G. D. D., Barlev, N. A., Macip, S.|Cancer Research current issue|Labels: Btk, P53
p53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress. Inhibiting BTK reduced both p53-dependent senescence and apoptosis. Further, BTK expression also upregulated DNA damage signals and apoptosis. We conclude that despite being involved in oncogenic signals in blood malignancies, BTK has antineoplastic properties in other contexts, such as the enhancement of p53's tumor suppressor responses. Along with evidence that BTK expression correlates with good prognosis in some epithelial tumors, our findings may encourage a reevaluation of the clinical uses of BTK inhibitors in cancer therapy. Cancer Res; 76(18); 5405–14. ©2016 AACR.
Thursday, September 15, 2016 6:45 AM|El-Deiry, W. S.|Cancer Research recent issues|Labels: P53
p21 (WAF1/CIP1; CDKN1a) is a universal cell-cycle inhibitor directly controlled by p53 and p53-independent pathways. Knowledge of the regulation and function of p21 in normal and cancer cells has opened up several areas of investigation and has led to novel therapeutic strategies. The discovery in 1993 and subsequent work on p21 has illuminated basic cellular growth control, stem cell phenotypes, the physiology of differentiation, as well as how cells respond to stress. There remain open questions in the signaling networks, the ultimate role of p21 in the p53-deficiency phenotype in the context of other p53 target defects, and therapeutic strategies continue to be a work in progress. Cancer Res; 76(18); 5189–91. ©2016 AACR.See related article by El-Deiry et al., Cancer Res 1994;54:1169–74.Visit the Cancer Research 75th Anniversary timeline.
Wednesday, September 14, 2016 10:11 PM|Chu-Xia Deng|International Journal of Biological Sciences|Labels: P53

SIRT1 has been considered as a tumor promoter because of its increased expression in some types of cancers and its role in inactivating proteins that are involved in tumor suppression and DNA damage repair. However, recent studies demonstrated that SIRT1 levels are reduced in some other types of cancers, and that SIRT1 deficiency results in genetic instability and tumorigenesis, while overexpression of SIRT1 attenuates cancer formation in mice heterozygous for tumor suppressor p53 or APC. Here, I review these recent findings and discuss the possibility that activation of SIRT1 both extends lifespan and inhibits cancer formation.

Wednesday, September 14, 2016 5:53 PM|Yuan-fang Li, Dan-dan Wang, Bai-wei Zhao, Wei Wang, Chun-yu Huang, Yong-ming Chen, Yan Zheng, Rajiv Prasad Keshari, Jian-chuan Xia, Zhi-wei Zhou|International Journal of Biological Sciences|Labels: P53, gastric

COP1 (constitutive photomorphogenic 1, also known as RFWD2) is a p53-targeting E3 ubiquitin ligase containing RING-finger, coiled-coil, and WD40-repeat domains. Recent studies have identified that COP1 is overexpressed in several cancer types and that increased COP1 expression promotes cell proliferation, cell transformation, and tumor progression. In the present study, we investigated the expression and prognostic value of COP1 in primary gastric cancer. To investigate the role of the COP1 gene in primary gastric cancer pathogenesis, real-time quantitative PCR and western blotting were performed to examine COP1 expression in paired cancerous and matched adjacent noncancerous gastric tissues. The results revealed high COP1 mRNA (P=0.030) and protein (P=0.008) expression in most tumor-bearing tissues compared with the matched adjacent non-tumor tissues. The correlated protein expression analysis revealed a negative correlation between COP1 and p53 in gastric cancer samples (P=0.005, r=-0.572). Immunohistochemical staining of gastric cancer tissues from the same patient showed a high COP1 expression and a low p53 expression. To further investigate the clinicopathological and prognostic roles of COP1 expression, we performed immunohistochemical analysis of 401 paraffin-embedded gastric cancer tissue blocks. The data revealed that high COP1 expression was significantly correlated with T stage (P=0.030), M stage (P=0.048) and TNM stage (P=0.022). Consistent with these results, we found that high expression of COP1 was significantly correlated with poor survival in gastric cancer patients (P<0.001). Cox regression analyses showed that COP1 expression was an independent predictor of overall survival (P<0.001). Our data suggest that COP1 could play an important role in gastric cancer and might serve as a valuable prognostic marker and potential target for gene therapy in the treatment of gastric cancer.

Wednesday, September 14, 2016 4:23 PM|C. Li|JournalTOCs API - Journal of Investigative Dermatology (875 articles)|Labels: P53, melanoma

471 Down-regulated TRPV1 contributes to the progression of melanoma
Y. Yang J. Ma, W. Guo, G. Zhu, T. Gao, C. Li
Journal of Investigative Dermatology, Vol. 136, No. 9 (2016) pp. S241 -
To identify the function of TRPV1 in the progression of melanoma and investigate the underlying mechanism. Immunofluorescence, qRT-PCR and Western Blot were performed to detect the expression of TRPV1 in tissue samples of melanocytic nevus, primary melanoma, metastatic melanoma as well as in melanoma cell lines. In addition, using CCK8 assay, Edu and flow cytometry, we identified the effect of TRPV1-specific agonist, capsaicin, on the proliferation and apoptosis of melanoma cells. To identify the molecular mechanism by which TRPV1 regulates the progression of melanoma, we performed western blot assay to detect the expression of p53, PARP, Bcl2, Bax in TRPV-1 activated melanoma cells exposed to Calcinerin blocker FK506.

Wednesday, September 14, 2016 5:40 AM|Hiroyuki Minemura, Kiyoshi Takagi, Ai Sato, Hikaru Takahashi, Yasuhiro Miki, Yukiko Shibahara, Mika Watanabe, Takanori Ishida, Hironobu Sasano, Takashi Suzuki|Cancer Science|Labels: P53, breast cancer
CITED2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2) is a member of CITED family and involved in various cellular functions during development and differentiation. Mounting evidence suggests importance of CITEDs in the progression of human malignancies, but significance of CITED2 protein has not yet been examined in breast carcinoma. Therefore, in this study, we examined clinical significance and biological functions of CITED2 in breast carcinoma by immunohistochemistry and in vitro studies. CITED2 immunoreactivity was detected in the breast carcinoma tissues, and it was significantly higher compared to the morphologically normal mammary glands. CITED2 immunoreactivity was significantly associated with stage, pathological T factor, lymph node metastasis, histological grade, HER2 and Ki-67, and inversely correlated with estrogen receptor. Moreover, the immunohistochemical CITED2 status was significantly associated with increased incidence of recurrence and breast cancer-specific death of the breast cancer patients, and multivariate analyses demonstrated CITED2 status as an independent worse prognostic factor for disease-free and breast cancer-specific survival. Subsequent in vitro experiments showed that CITED2 expression significantly increased proliferation activity and migration property in MCF-7 and SKBR-3 breast carcinoma cells. Moreover, CITED2 caused chemoresistance to epirubicin and 5-fluorouracil, but not paclitaxel, in these cells, and it inhibited p53 accumulation after 5-fluorouracil treatment in MCF-7 cells. These results suggest that CITED2 plays important roles in the progression and chemoresistance of breast carcinoma and CITED2 status is a potent prognostic factor in breast cancer patients. This article is protected by copyright. All rights reserved.
Wednesday, September 14, 2016 5:40 AM|Akifumi Endo, Daisuke Tomizawa, Yuki Aoki, Tomohiro Morio, Shuki Mizutani, Masatoshi Takagi|Cancer Science|Labels: P53, AML
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has been rarely reported. We identified a novel EWSR1 associated chimeric fusion gene in a patient with acute myeloid leukemia (AML) harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired-end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation-specific (ETS) transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21-dependent pathway. The injection of EWSR1/ELF5-transduced NIH3T3 cells into NSG-SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5. This article is protected by copyright. All rights reserved.
Tuesday, September 13, 2016 11:38 PM|Jianming He, Xi Liang, Fen Luo, Xuedan Chen, Xueqing Xu, Fengchao Wang, Zhenping Zhang|Journal of Cancer|Labels: caspase, P53, CRC

Three-dimensional (3D) culture models represent a better approximation of solid tumor tissue architecture, especially cell adhesion, in vivo than two-dimensional (2D) cultures do. Here, we explored the role of architecture in chemosensitivity to platinum in colon cancer. Under the 3D culture condition, colon cancer cells formed multicellular spheroids, consisting of layers of cells. 3D cultures displayed significantly decreased sensitivity to platinum compared with 2D cultures. Platinum increased p53 in a dose-dependent and time-dependent manner. There was no detectable difference in basal p53 levels between 3D cultures and 2D cultures but cisplatin induced less p53 in both HCT116 3D cultures and LoVo 3D cultures. It was not due to cisplatin concentration because cisplatin induced similar γ-H2AX in 3D vs 2D. Knockdown of p53 significantly decreased sensitivity to platinum in 3D cultures. Knockdown of p53 decreased cleaved caspase 3 and apoptosis induced by cisplatin. These findings indicate that 3D architecture confers decreased chemosensitivity to platinum and p53 is involved in the mechanism. Knockdown of p53 decreased cisplatin's induction of c-Jun N-terminal kinase 1/2 (JNK1/2) activation, whereas inhibition of JNK1/2 activation increased chemosensitivity. Inhibition of p38 activation decreased cisplatin's induction of p53, but no difference in p38 activation by cisplatin was observed between 2D cultures and 3D cultures. Taken together, our results suggest that p53 is involved in a 3D architecture-mediated decrease in chemosensitivity to platinum in colon cancer. Mitogen-activated protein kinases (JNK1/2 and p38) do not play a dominant role in the mechanism.

Tuesday, September 13, 2016 11:38 PM|Miroslav Genov, Birgit Kreiseder, Michael Nagl, Elisabeth Drucker, Martina Wiederstein, Barbara Muellauer, Julia Krebs, Teresa Grohmann, Dagmar Pretsch, Karl Baumann, Markus Bacher, Alexander Pretsch, Christoph Wiesner|Journal of Cancer|Labels: NFKb, P53, ROS, melanoma

Background: Malignant melanoma is an aggressive type of skin cancer with high risk for metastasis and chemoresistance. Disruption of tightly regulated processes such as cell cycle, cell adhesion, cell differentiation and cell death are predominant in melanoma development. So far, conventional treatment options have been insufficient to treat metastatic melanoma and survival rates are poor. Anthraquinone compounds have been reported to have anti-tumorigenic potential by DNA-interaction, promotion of apoptosis and suppression of proliferation in various cancer cells.

Methods: In the current study, the racemic tetrahydroanthraquinone derivative (±)-4-deoxyaustrocortilutein (4-DACL) was synthesized and the cytotoxic activity against melanoma cells and melanoma spheroids determined by CellTiter-Blue viability Assay and phase contrast microscopy. Generation of reactive oxygen species (ROS) was determined with CellROX Green and Deep Red Reagent kit and microplate-based fluorometry. Luciferase reporter gene assays for nuclear factor kappa B (NF-κB) and p53 activities and western blotting analysis were carried out to detect the expression of anti-proliferative or pro-apoptotic (p53, p21, p27, MDM2, and GADD45M) and anti-apoptotic (p65, IκB-α, IKK) proteins. Cell cycle distribution and apoptosis rate were detected by flow cytometry, the morphological changes visualized by fluorescence microscopy and the activation of different caspase cascades distinguished by Caspase Glo 3/7, 8 and 9 Assays.

Results: We demonstrated that 4-DACL displayed high activity against different malignant melanoma cells and melanoma spheroids and only low toxicity to melanocytes and other primary cells. In particular, 4-DACL treatment induced mitochondrial ROS, reduced NF-κB signaling activity and increased up-regulation of the cell cycle inhibitors cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) and the tumor suppressor protein p53 in a dose-dependent manner, which was accompanied by decreased cell proliferation and apoptosis via the intrinsic pathway.

Conclusion: According to these results, we suggest that 4-DACL may be a promising therapeutic agent for the treatment of malignant melanoma.

Tuesday, September 13, 2016 8:19 PM|Ammara Abdullah, Sanam Sane, Jessica L Freeling, Hongmin Wang, Dong Zhang, Khosrow Rezvani|Journal of Cancer (RSS 2.0)|Labels: P53, CRC

The subcellular localization, expression level, and activity of anti-cancer proteins alter in response to intrinsic and extrinsic cellular stresses to reverse tumor progression. The purpose of this study is to determine whether UBXN2A, an activator of the p53 tumor suppressor protein, has different subcellular compartmentalization in response to the stress of DNA damage. We measured trafficking of the UBXN2A protein in response to two different DNA damage stresses, UVB irradiation and the genotoxic agent Etoposide, in colon cancer cell lines. Using a cytosol-nuclear fractionation technique followed by western blot and immunofluorescence staining, we monitored and quantitated UBXN2A and p53 proteins as well as p53's downstream apoptotic pathway.

We showed that the anti-cancer protein UBXN2A acts in the early phase of cell response to two different DNA damage stresses, being induced to translocate into the cytoplasm in a dose- and time-dependent manner. UVB-induced cytoplasmic UBXN2A binds to mortalin-2 (mot-2), a known oncoprotein in colon tumors. UVB-dependent upregulation of UBXN2A in the cytoplasm decreases p53 binding to mot-2 and activates apoptotic events in colon cancer cells. In contrast, the shRNA-mediated depletion of UBXN2A leads to significant reduction in apoptosis in colon cancer cells exposed to UVB and Etoposide. Leptomycin B (LMB), which was able to block UBXN2A nuclear export following Etoposide treatment, sustained p53-mot-2 interaction and had partially antagonistic effects with Etoposide on cell apoptosis. The present study shows that nucleocytoplasmic translocation of UBXN2A in response to stresses is necessary for its anti-cancer function in the cytoplasm. In addition, LMB-dependent suppression of UBXN2A's translocation to the cytoplasm upon stress allows the presence of an active mot-2 oncoprotein in the cytoplasm, resulting in p53 sequestration as well as activation of other mot-2-dependent growth promoting pathways.

Tuesday, September 13, 2016 8:19 PM|Chao Wang, Weiwei Feng, Chuyao Zhang|Journal of Cancer (RSS 2.0)|Labels: P53, endometrial cancer

Background: Since more and more evidences support that NUMB orchestrates many cell physiological and pathological processes of diseases including cancer, based on our previous work, we studied deeply the function of NUMB in endometrial cancer (EC) and tried to understand the mechanism of NUMB's nucleus translocation which might be relative to the occurrence of EC and will contribute to find a new targeting therapeutic strategy for EC.

Methods: Immunohistochemistry was employed to test NUMB and HDM2 expression in endometrial cancer tissue from clinical patients. CCK-8 assay, cell cycle tested by Flow cytometer and PCNA determined by RT-PCR were employed to test the effects of NUMB on cell proliferation and apoptosis. In order to investigate the mechanism how NUMB, HDM2 and p53 interact in EC cell, western blot, Co-IP and immunofluorescent were used to observe the combination and location of NUMB, HDM2 and p53 as well as the interaction among them.

Results: Both NUMB and HDM2 expressed greater in endometrial cancer tissues than in normal endometrial tissues. Overexpression of NUMB induced apoptosis in Ishikawa cell while inhibition of NUMB increased cell proliferation. NUMB could combine HDM2 and p53, moreover the PTB domain of NUMB is the main site combining with p53. The effects of NUMB in cell was closely associated with p53. Not only NUMB regulated P53 expression level but also NUMB acts depending on P53, in turn p53 impacted the NUMB level as a feedback. Overexpression of NUMB could not bring itself into nuclear. Both siHDM2 and siP53 didn't bring NUMB into nucleus, However overexpression of HDM2 and p53 increased the NUMB level in nucleus, and the NUMB nuclear location induced by overexpression of HDM2 was stronger than that of p53 overexpression.

Conclusions: Based on present data, we think NUMB acts as an anti-oncogene role and could regulate p53 level and function in endometrial cancer like in other cancers, meanwhile, the function of NUMB depend on P53. On the other hand, the location of NUMB could be regulated mainly by HDM2. So far we are not able to explain why endometrial cancer patients had high NUMB expression level since NUMB was regarded as a tumor suppressor, which is worthy studying further to explore underlying mechanism.

Tuesday, September 13, 2016 8:19 PM|Chengmeng Jin, Wei Yu, Xiaoyan Lou, Fan Zhou, Xu Han, Na Zhao, Biaoyang Lin|Journal of Cancer|Labels: Bcl-2, P53, ovarian cancer

Ubiquitin carboxyl terminal hydrolase 1 (UCHL1) catalyzes the hydrolysis of COOH-terminal ubiquityl esters and amides. It has been reported as either an oncogene or a tumor suppressor in cancers. However, UCHL1's role in ovarian cancer is still unclear. Therefore, we conducted an analysis to understand the role of UCHL1 in ovarian cancer. Firstly, we detected UCHL1 promoter methylation status in 7 ovarian cancer cell lines. 4 of them with UCHL1 silencing showed heavy promoter methylation while the other 3 with relative high UCHL1 expression showed little promoter methylation. Then we reduced UCHL1 expression in ovarian cancer cell line A2780 and IGROV1 and found that inhibition of UCHL1 promoted cell proliferation by increasing cells in S phases of cell cycle. Knockdown of UCHL1 also reduced cell apoptosis and contributed to cisplatin resistance. Furthermore, the expression level of UCHL1 in several ovarian cancer cell lines correlated negatively with their cisplatin resistance levels. Microarray data revealed that UCHL1 related genes are enriched in apoptosis and cell death gene ontology (GO) terms. Several apoptosis related genes were increased after UCHL1 knockdown, including apoptosis regulator BCL2, BCL11A, AEN and XIAP. Furthermore, we identified up-regulation of Bcl-2 and pAKT as well as down-regulation of Bax in UCHL1 knockdown cells, while no significant alteration of p53 and AKT1 was found. This study provides a new and promising strategy to overcome cisplatin resistance in ovarian cancer via UCHL1 mediated pathways.

Tuesday, September 13, 2016 8:19 PM|Joel G. Turner, Jana Dawson, Michael F. Emmons, Christopher L. Cubitt, Michael Kauffman, Sharon Shacham, Lori A. Hazlehurst, Daniel M. Sullivan|Journal of Cancer|Labels: P53, MM

Multiple myeloma (MM) remains an incurable disease despite improved treatments, including lenalidomide/pomalidomide and bortezomib/carfilzomib based therapies and high-dose chemotherapy with autologous stem cell rescue. New drug targets are needed to further improve treatment outcomes. Nuclear export of macromolecules is misregulated in many cancers, including in hematological malignancies such as MM. CRM1 (chromosome maintenance protein-1) is a ubiquitous protein that exports large proteins (>40 kDa) from the nucleus to the cytoplasm. We found that small-molecule Selective Inhibitors of Nuclear Export (SINE) prevent CRM1-mediated export of p53 and topoisomerase IIα (topo IIα). SINE's CRM1-inhibiting activity was verified by nuclear-cytoplasmic fractionation and immunocytochemical staining of the CRM1 cargoes p53 and topo IIα in MM cells. We found that SINE molecules reduced cell viability and induced apoptosis when used as both single agents in the sub-micromolar range and when combined with doxorubicin, bortezomib, or carfilzomib but not lenalidomide, melphalan, or dexamethasone. In addition, CRM1 inhibition sensitized MM cell lines and patient myeloma cells to doxorubicin, bortezomib, and carfilzomib but did not affect peripheral blood mononuclear or non-myeloma bone marrow mononuclear cells as shown by cell viability and apoptosis assay. Drug resistance induced by co-culture of myeloma cells with bone marrow stroma cells was circumvented by the addition of SINE molecules. These results support the continued development of SINE for patients with MM.

Wednesday, August 31, 2016 10:05 PM|Sandhu, V., Wedge, D. C., Bowitz Lothe, I. M., Labori, K. J., Dentro, S. C., Buanes, T., Skrede, M. L., Dalsgaard, A. M., Munthe, E., Myklebost, O., Lingȷarde, O. C., Borresen–Dale, A.–L., Ikdahl, T., Van Loo, P., Nord, S., Kure, E. H.|Cancer Research recent issues|Labels: P53, WNT, pancreatic cancer, preclinical
Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n = 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged. Cancer Res; 76(17); 5092–102. ©2016 AACR.
Friday, August 26, 2016 1:20 PM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: P53, lung cancer

Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 16 September 2016 Source:Biochemical and Biophysical Research Communications, Volume 478, Issue 2 Author(s): En-Pan Mo, Rong-Rong Zhang, Jun Xu, Huan Zhang, Xiao-Xiong Wang, Qiu-Tong Tan, Fang-Lan Liu, Ren-Wang Jiang, Shao-Hui Cai Calotropin (M11), an active compound isolated from Asclepias curasavica L., was found to exert strong inhibitory and pro-apoptotic activity specifically against cisplatin-induced resistant non-small cell lung cancer (NSCLC) cells (A549/CDDP). Molecular mechanism study revealed that M11 induced cell cycle arrest at the G2/M phase through down-regulating cyclins, CDK1, CDK2 and up-regulating p53 and p21. Furthermore, M11 accelerated apoptosis through the mitochondrial apoptotic pathway which was accompanied by increase Bax/Bcl-2 ratio, decrease in mitochondrial membrane potential, increase in reactive oxygen species production, activations of caspases 3 and 9 as well as cleavage of poly ADP-ribose polymerase (PARP). The activation and phosphorylation of JNK was also found to be involved in M11-induced apoptosis, and SP610025 (specific JNK inhibitor) partially prevented apoptosis induced by M11. In contrast, all of the effects that M11 induce cell cycle arrest and apoptosis in A549/CDDP cells were not significant in A549 cells. Drugs with higher sensitivity against resistant tumor cells than the parent cells are rather rare. Results of this study supported the potential application of M11 on the non-small lung cancer (NSCLC) with cisplatin resistance.

Thursday, August 25, 2016 2:41 AM|Yoshikazu Johmura, Makoto Nakanishi|Cancer Science|Labels: P53
Cellular senescence is a state of durable cell cycle arrest with metabolic activities distinct from those of the proliferative state. Since senescence was originally reported to be induced by various genotoxic stressors, such as telomere erosion and oncogenic signaling, it has been proposed to play a pivotal role in aging-related changes and as an anti-tumorigenic barrier in vivo. However, the mechanisms underlying its induction and maintenance remain entirely elusive. We have recently found that abrupt activation of p53 at G2 results in a cell skipping mitosis and subsequently undergoing senescence. Surprisingly, we have also found that downregulation of p53 by SCFFbxo22 is crucial for the induction of an senescence-associated phenotype. In this review, we provide an overview of recent advances in understanding the mechanisms underlying the timing and magnitude of activation of p53 during senescence. This article is protected by copyright. All rights reserved.
Sunday, August 14, 2016 10:05 PM|Stelloo, E., Nout, R. A., Osse, E. M., Jürgenliemk-Schulz, I. J., Jobsen, J. J., Lutgens, L. C., van der Steen-Banasik, E. M., Nijman, H. W., Putter, H., Bosse, T., Creutzberg, C. L., Smit, V. T. H. B. M.|Clinical Cancer Research recent issues|Labels: P53, endometrial cancer

Purpose: Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy.

Experimental Design: Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, β-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared.

Results: Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high-intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant).

Conclusions: Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16); 4215–24. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Wu, S. P., Pfeiffer, R. M., Ahn, I. E., Mailankody, S., Sonneveld, P., van Duin, M., Munshi, N. C., Walker, B. A., Morgan, G., Landgren, O.|Clinical Cancer Research recent issues|Labels: Myc, P53, MM

Purpose: The poor prognosis of multiple myeloma with t(4;14) is driven by the fusion of genes encoding multiple myeloma SET domain (MMSET) and immunoglobulin heavy chain. Specific genes affected by MMSET and their clinical implications in non-MMSET myeloma remain undetermined.

Experimental Design: We obtained gene expression profiles of 1,032 newly diagnosed myeloma patients enrolled in Total Therapy 2, Total Therapy 3, Myeloma IX, and HOVON65-GMMGHD4 trials and 156 patients from Multiple Myeloma Resource Collection. Probes that correlated most with MMSET myeloma were selected on the basis of a multivariable linear regression and Bonferroni correction and refined on the basis of the strength of association with survival in non-MMSET patients.

Results: Ten MMSET-like probes were associated with poor survival in non-MMSET myeloma. Non-MMSET myeloma patients in the highest quartile of the 10-gene signature (MMSET-like myeloma) had 5-year overall survival similar to that of MMSET myeloma [highest quartile vs. lowest quartile HR = 2.0; 95% confidence interval (CI), 1.5–2.8 in MMSET-like myeloma; HR = 2.3; 95% CI, 1.6–3.3 in MMSET myeloma]. Analyses of MMSET-like gene signature suggested the involvement of p53 and MYC pathways.

Conclusions: MMSET-like gene signature captures a subset of high-risk myeloma patients underrepresented by conventional risk stratification platforms and defines a distinct biologic subtype. Clin Cancer Res; 22(16); 4039–44. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Parasido, E. M., Sripadhan, P., Schlegel, R., Pishvaian, M. J., Brody, J., Winter, J., Albanese, C.|Clinical Cancer Research recent issues|Labels: P53, RAS, pancreatic cancer

Background: Pancreatic adenocarcinoma (PA) is the fourth leading cause of cancer related death in the USA. Patients diagnosed with this disease can expect a 1-year survival rate of approximately 10%. One of the main reasons of the high mortality observed within PA is failure on first-line therapies. Current PA treatment involves Gemcitabine, a nucleoside analog that showed improvement in overall survival. Recently this drug has been used in combination with nab-paclitaxel, 5-FU, Erlotinib and MEK inhibitors. However, a growing number of patients have shown resistance to these regimes. A more comprehensive understanding of resistance mechanisms will enhance treatment choice and clinical responses, and this remains an area of intense investigation. However much of the data available on PA drug targets and efficacy come from commercially available pancreatic cell lines, a main limitation in PA research, as these lines do not accurately represent a given patients' tumor, underscoring the need for the development and use of patient-specific primary epithelial PA cells. In our current study we present the use of patient-derived primary PA cells as a model system for basic and translational research as well as personalized therapeutic approaches.

Methods: Patients' biopsies were collected after surgery and long-term cultures of PA cells were established using the conditional reprogramming of cells (CRC) approach. To date, six primary lines have been continuous culture for over 6 month. KRAS and p53 sequencing verified the PA origin of both the patient sample and the matched CRC lines. CRC karyotyping was also performed to confirm the absence of normal cells as well as to validate the long-term genomic integrity of the lines in culture. In order to evaluate patient-specific differences in treatment response, the IC50's for gemcitabine, nab-paclitaxel (Abraxane) and the MEK inhibitor, Trametinib, were determined. To better understand treatment resistance mechanisms, new drug resistance approaches were developed and multiple drug-resistant clones per primary cell line were established, and their resistance verified. Gemcitabine activity was also evaluated in combination with Abraxane and Trematenib in both parental and resistant-clone cell lines. In addition, novel three-dimensional (3D) organoid cultures have been established from the two dimensional (2D) CRC cultures in order to verify the constancy of the model.

Results: We established KRAS-mutant primary cell lines derived from patients' PA specimens. The cell lines' karyotype showed stability over multiple passages covering more than 6 months in continuous 2D culture. Five Abraxane resistant clones have been derived to date from two different parent cell lines and two gemcitabine resistant clones derived from one of these cell lines. The clones tested were 3 to 1000 times less sensitive to the drugs when compared to the parents. Notably, the Abraxane resistant clones also showed a greater resistance to Gemcitabine as compared to the parent line. In addition, the PA lines also showed an overall increasing sensitivity to Gemcitabine when pre- or co-treated with Trematenib. Molecular and genetic analyses are being performed to identify potential biomarkers of high therapeutic value.

Conclusion: Taken together, the ease of culture, the genetic stability, the medium to high throughput ability to identify differences between patients sensitivity to FDA approved drugs, all confirm the power of this technology for on-demand in vitro use in PA research. Our approach now enables the high-resolution experiments necessary to better understand the underlying drug sensitivity and resistance mechanisms that directly affect clinical outcomes.

Citation Format: Erika M. Parasido, Praathibha Sripadhan, Richard Schlegel, Michael J. Pishvaian, Jonathan Brody, Jordan Winter, Christopher Albanese. Patient-derived Pancreatic Adenocarcinoma cells: A new model system to define chemotherapy resistance mechanisms and to improve targeted personalized treatment. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B15.

Thursday, August 4, 2016 1:31 AM|Ken Saito, Hidekazu Iioka, Chie Kojima, Mikako Ogawa, Eisaku Kondo|Cancer Science|Labels: P53
p14ARF is one of the major tumor suppressors conventionally identified both as the mdm2-binding molecule restoring p53 function in the nucleus, and as a nucleophosmin-binding partner inside the nucleolous to stabilize ribosomal RNA. However, its recently reported mitochondrial localization has pointed to novel properties as a tumor suppressor. At the same time, functional peptides are gaining much attention in nanomedicine for their in vivo utility as non-invasive biologics. We previously reported the p14ARF-specific peptide that restored the sensitivity to gefitinib on the gefitinib-resistant lung cancer cells. Based on the information of this prototype peptide, here we generated the more powerful anti-tumor peptide “r9-CatB-p14 MIS,” which comprises the minimal inhibitory sequence of the mitochondrial targeting p14ARF protein in combination with the proteolytic cleavage site for cathepsin B, which is activated in various tumor cells, fused with the nine-polyarginine-domain for cell penetration, and demonstrated its novel action of regulating mitochondrial function in accordance with localization of endogenous p14ARF. The p14 MIS peptide showed a potent tumor inhibiton in vitro and in vivo against not only lung cancer cells but also tumor cells of diverse lineages, via modulating mitochondrial membrane potential, with minimal cytotoxicity to non-neoplastic cells and tissues. Hence, this mitochondrially targeted p14 peptide agent provides a novel basis for non-invasive peptide-based antitumor therapeutics. Action mode of the novel tumor suppressor peptide, “p14 MIS”, on cancer cells.
Monday, August 1, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: Myc, P53, CML

MYC and p53 are critical nodes in chronic myeloid leukemia (CML) leukemic stem cells.

Wednesday, July 27, 2016 11:11 AM|KUNIZAKI, M., SAWAI, T., TAKESHITA, H., TOMINAGA, T., HIDAKA, S., TO, K., MIYAZAKI, T., HAMAMOTO, R., NANASHIMA, A., NAGAYASU, T.|Anticancer Research recent issues|Labels: CEA, P53, CRC

Background: Serum p53 antibody (s-p53Ab), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were investigated to evaluate the significance of these singly and combined tumor markers in the diagnosis and prognosis of colorectal cancer (CRC). Patients and Methods: Preoperative serum samples were obtained from 170 patients with histologically confirmed CRC, including 28 (16%) with stage I. s-p53Ab was assessed using the MESACUP Kit II, that is a new and highly specific version of a quantitative p53-Abs enzyme-linked immunosorbent assay. Results: s-p53Ab was detected in 30.6% (52 out of 170) of patients with CRC, including 31.9% (29/91) of patients with early-stage CRC. The positive rates for CEA and CA19-9 of patients with CRC were 28.8% (49/170) and 22.9% (39/170), respectively. Combining use of s-p53-Ab with CEA increased the positive rate of a diagnosis of CRC to 48.8%. Positivity for s-p53Ab in CRC did not correlate with overall survival. On the other hand, Cox regression analysis of this series revealed that high levels of CEA served as an independent prognostic factor for CRC. Kaplan-Meier analysis revealed significant differences between patients with elevated s-p53Ab and CEA and those with elevated levels of either one or neither of these factors (p<0.001). Conclusion: The diagnostic rate of s-p53Ab was better than that of CEA and CA19-9 in patients with early-stage CRC. Combined detection of s-p53Ab and CEA can improve diagnostic sensitivity and may permit more accurate stratification of patients with CRC.

CONCLUSIONSThe type of treatment received did not improve outcomes in younger or older patients with TP53‐mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Friday, July 22, 2016 8:03 AM|Dalin, M. G., Desrichard, A., Katabi, N., Makarov, V., Walsh, L. A., Lee, K.-W., Wang, Q., Armenia, J., West, L., Dogan, S., Wang, L., Ramaswami, D., Ho, A. L., Ganly, I., Solit, D. B., Berger, M. F., Schultz, N. D., Reis-Filho, J. S., Chan, T. A., Morris, L. G. T.|Clinical Cancer Research Online First Articles|Labels: MapK, P53, salivary duct cancer

Purpose: Salivary duct carcinoma (SDC) is an aggressive salivary malignancy, which is resistant to chemotherapy and has high mortality rates. We investigated the molecular landscape of SDC, focusing on genetic alterations and gene expression profiles.

Experimental Design: We performed whole-exome sequencing, RNA sequencing, and immunohistochemical analyses in 16 SDC tumors and examined selected alterations via targeted sequencing of 410 genes in a second cohort of 15 SDCs.

Results: SDCs harbored a higher mutational burden than many other salivary carcinomas (1.7 mutations/Mb). The most frequent genetic alterations were mutations in TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) tumors had alterations in either MAPK (BRAF/HRAS/NF1) genes or ERBB2. Potentially targetable alterations based on supportive clinical evidence were present in 61% of tumors. Androgen receptor (AR) was overexpressed in 75%; several potential resistance mechanisms to androgen deprivation therapy (ADT) were identified, including the AR-V7 splice variant (present in 50%, often at low ratios compared with full-length AR) and FOXA1 mutations (10%). Consensus clustering and pathway analyses in transcriptome data revealed striking similarities between SDC and molecular apocrine breast cancer.

Conclusions: This study illuminates the landscape of genetic alterations and gene expression programs in SDC, identifying numerous molecular targets and potential determinants of response to AR antagonism. This has relevance for emerging clinical studies of ADT and other targeted therapies in SDC. The similarities between SDC and apocrine breast cancer indicate that clinical data in breast cancer may generate useful hypotheses for SDC. Clin Cancer Res; 1–11. ©2016 AACR.

Thursday, June 30, 2016 11:00 PM|Yi, Ke; Yang, LingYun; Lan, Zhu; Xi, MingRong|International Journal of Gynecological Cancer - Current Issue|Labels: P53, endometrial cancer
imageAbstract: Polymorphism of p53 codon 72 plays an important role in pathogenesis and development of cancer. Published data on the association between the p53 codon 72 polymorphism and endometrial cancer risk are controversial. A meta-analysis was performed to assess whether the polymorphism of p53 codon 72 is associated with endometrial cancer risk. Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Databases were searched to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for p53 codon 72 polymorphism and endometrial cancer were appropriately derived from fixed-effects or random effects models. A total of 12 studies were enrolled in this meta-analysis. The pooled analyses revealed that p53 codon 72 polymorphism was not associated with endometrial cancer risk. Stratified analysis by Hardy-Weinberg equilibrium exhibited a significantly increased risk of endometrial cancer among studies deviated from Hardy-Weinberg equilibrium in heterozygote comparison (Pro/Arg vs Arg/Arg; OR, 0.61; 95% CI, 0.42–0.87) and dominant model (Pro/Pro + Pro/Arg vs Arg/Arg; OR, 0.66; 95% CI, 0.47–0.92). This study indicated that the p53 codon 72 polymorphism may not be associated with endometrial cancer risk.
Thursday, June 30, 2016 10:05 PM|Corcoran, N. M., Clarkson, M. J., Stuchbery, R., Hovens, C. M.|Clinical Cancer Research recent issues|Labels: P53, PARP

The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage repair (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate, however, that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family. Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden. Targeting DNA repair–deficient tumors with drugs that take advantage of the fundamental differences between normal repair–proficient cells and repair-deficient tumors offers new avenues for treating advanced disease in the future. Clin Cancer Res; 22(13); 3132–7. ©2016 AACR.

Sunday, May 29, 2016 1:00 AM|Seema Patel, Neeta Singh, Lalit Kumar|International Journal of Cancer Therapy and Oncology|Labels: P53, ovarian cancer

Purpose: Epithelial ovarian cancer is the most common ovarian cancer and has life threatening implications. Despite the progress in surgical and therapeutic strategies, resistance to chemotherapy is still a major concern. Chemotherapeutic agents cause cytotoxicity, primarily by the induction of apoptosis. The status of p53 is a key factor in determining the efficacy of apoptotic signaling. p53 is the most commonly mutated tumor suppressor gene in ovarian cancer. Metformin (an antidiabetic drug) has shown putative effects in many solid tumors. Hence we aimed to study the role of metformin in p53 mutated cancer cells.

Methods: SKOV3 and OAW42 ovarian cancer cell line were used. The cancer cells were treated with metformin. MTT, Flow cytometry and Western blotting were used to characterize the effects of the different treatments.

Results: Metformin treatment leads to cell cycle arrest in the G0/G1, S and G2/M phase of the cell cycle in SKOV3 and OAW42 respectively. Moreover, there was upregulation of Bax and downregulation of Bcl-2 protein and increased apoptosis in SKOV3 and OAW42 ovarian cancer cells.

Conclusion: These findings support the potential of metformin to be used as chemoadjuvant and reflects its ability to sensitize cancer cells to apoptosis independent of p53 status.

Sunday, March 20, 2016 4:00 PM|Biochemical and Biophysical Research communications|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: P53
Authors: Li Y, Ma C, Zhou T, Liu Y, Sun L, Yu Z Abstract Tripartite-motif protein family member 65 (TRIM65) is an important protein involved in white matter lesion. However, the role of TRIM65 in human cancer remains less understood. Through the Cancer Genome Atlas (TCGA) gene alteration database, we found that TRIM65 is upregulated in a significant portion of non-small cell lung carcinoma (NSCLC) patients. Our cell growth assay revealed that TRIM65 overexpression promotes cell proliferation, while knockdown of TRIM65 displays opposite effect. Mechanistically, TRIM65 binds to p53, one of the most critical tumor suppressors, and serves as an E3 ligase toward p53. Consequently, TRIM65 inactivates p53 through facilitating p53 poly-ubiquitination and proteasome-mediated degradation. No...
Wednesday, March 16, 2016 4:00 PM|Biochemical and Biophysical Research communications|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: Bcl-2, P53, lung cancer
Authors: Matsumoto M, Nakajima W, Seike M, Gemma A, Tanaka N Abstract Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53-dependent and -independent...
Wednesday, March 9, 2016 4:00 PM|International Journal of Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: AKT, P53, lung cancer
Authors: In JK, Kim JK, Oh JS, Seo DW Abstract In the present study, we investigated the effects and molecular mechanism of 5-caffeoylquinic acid (5-CQA), a natural phenolic compound isolated from Ligularia fischeri, on cell invasion, proliferation and adhesion in p53 wild-type A549 and p53-deficient H1299 non-small cell lung cancer (NSCLC) cells. 5-CQA abrogated mitogen-stimulated invasion, but not proliferation, in both A549 and H1299 cells. In addition, 5-CQA inhibited mitogen-stimulated adhesion in A549 cells only. Anti-invasive activity of 5-CQA in A549 cells was mediated by the inactivation of p70S6K-dependent signaling pathway. In contrast, in H1299 cells the inactivation of Akt was found to be involved in 5-CQA-mediated inhibition of cell invasion. Collectively, these findi...
Tuesday, March 1, 2016 4:00 PM|Journal of Cancer Research and Clinical Oncology|MedWorm: Vaccines|Comments|Labels: P53, ovarian cancer
Conclusion It is hypothesized that TF1 may confer tumour-promoting features, especially in a TP53 wild-type genetic background. In addition, TF1 is an attractive immunotherapeutic target. Whether those cases classified as TF1 positive and at the same time as moderately stained for p53 might particularly benefit from a future anti-TF1 antibody treatment or from TF1 vaccination therapy remains to be determined. (Source: Journal of Cancer Research and Clinical Oncology)
Monday, February 29, 2016 4:00 PM|Neoplasma|MedWorm: Cancer Therapy|Comments|Labels: P53, cervical cancer
This study revealed that uc.206 is significantly up-regulated in cervical cancer (CC) tissue and negatively correlates with the expression of the pro-apoptotic gene P53 in RNA level. We show that uc.206 specifically targets the 3' untranslated region (3'UTR) of P53 and regulates its expression. Inhibition of uc.206 effectively delays cervical cells proliferation and promotes apoptosis, accompanied by increased expression of P53 protein. Thus, these findings suggested that uc.206 acts as a novel oncogene by targeting the P53 gene and promoting CC cell growth, which might be beneficial for cervical cancer therapy. PMID: 26925787 [PubMed - as supplied by publisher] (Source: Neoplasma)
Thursday, February 18, 2016 4:00 PM|Journal of Biological Chemistry|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: P53, lung cancer
p53 inactivation is a hallmark in non-small-cell lung cancer (NSCLC). It is therefore highly desirable to develop tumor-specific treatment for NSCLC therapy by restoring p53 function. Herein, a novel naphthalimide compound, NA-17, was identified as a promising drug candidate in view of both its anticancer activity and mechanism of action. NA-17 exhibited strong anticancer activity on a broad range of cancer cell lines but showed low toxicity to normal cell lines, such as HL-7702 and WI-38. Moreover, NA-17 showed p53-dependent inhibition selectivity in different NSCLC cell lines due to the activation state of endogenous p53 in the background level. Further studies revealed that NA-17 caused cell cycle arrest at the G1 phase, changed cell size, and induced apoptosis and cell death by increas...

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Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: P53
The p53 tumor suppressor is a transcription factor that inhibits tumorigenesis by inducing cell cycle arrest or apoptosis in response to diverse stresses. In normal cells, p53 levels are tightly controlled by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 is overproduced in many human cancers, thereby impairing p53 function. Antagonists of p53-MDM2 interaction can enhance p53 activity and offer a novel approach to cancer therapy. The first potent and selective small-molecule inhibitors of p53-MDM2 binding, the nutlins, provided preclinical proof-of-concept for MDM2 antagonists as therapeutics for patients with tumors expressing wild-type p53. The nutlin family member idasanutlin (RG7388, RO5503781) is an oral small molecule inhibitor of MDM2 currently in cli...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: P53, CRC
TP53, a well-known tumour suppressor gene, is frequently inactivated by mutation or deletion in a majority of human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of p53 regulators and their poor drugability. Here, we demonstrate that genomic deletion of TP53 frequently encompasses neighbouring essential genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such an essential house-keeping gene that is virtually co-deleted with TP53 in many types of human cancer. It encodes the largest and catalytic subunit of RNA polymerase II complex, which is spe...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: P53, lung cancer
In conclusion, when combined with cisplatin or oxaliplatin, VAL-083 demonstrates superadditivity/synergy against NSCLC cells, independent of their p53 status. Further, VAL-083 in combination with cisplatin significantly increased median survival in vivo. These results strongly suggest a potential for VAL-083 as part of combination treatment with platinum drugs for NSCLC, including drug-resistant phenotypes. A clinical trial is planned under the context of the existing PRC approval to investigate these observations in a clinical setting. Results, if favorable, will support expanded clinical use of VAL-083 in PRC and will serve as the basis for global development of VAL-083 as a potentially important chemotherapeutic agent in the treatment of NSCLC.Citation Format: Anne Steino, Jeffrey A. Ba...