Oncology Intelligence

NFκB is a transcription factor that regulates cytokine production and cell survival. NF-κB is found in most animal cell types. Rapid-acting primary transcription factors, like NF-κB, do not require new protein synthesis in order to become activated, and include c-Jun, STATs, and nuclear hormone receptors. NFκB is a first responder in regulating the immune response to infection and regulates genes responsible for both the innate and adaptive immune response.(1) Activated NFκB upregulates genes involved in T-cell development, maturation, and proliferation.(1, 2) NFκB has also been implicated in processes of synaptic plasticity and memory, and cellular responses to stimuli such as stress, cytokines, free radicals, oxidized LDL, bacterial or viral antigens, ROS, TNFα, RANKL, IL-1α, bacterial lipopolysaccharides, isoproterenol, cocaine, ionizing radiation.(1,4,5)
NF-κB family members share structural homology with the retroviral oncoprotein v-Rel. There are five proteins in the mammalian NF-κB family: NFκB1, NFκB2, RelA, RelB, and c-Rel. Proteins of the NF-κB family share a Rel homology domain in their N-terminus. RelA, RelB, and c-Rel have a transactivation domain in their C-termini, wherease NFκB1 and NFκB2 are synthesized as large precursors, p105, and p100, which undergo processing to generate the mature NFκB subunits, p50 and p52, respectively.(1)
Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. When activated IκB kinase phosphorylates two serine residues located in an IκB regulatory domain which allows IκB inhibitors to be ubiquitinated and degraded. With the degradation of IκB, the NFκB complex is then freed to enter the nucleus. NFκB activates expression of its own repressor, IκBα. The newly synthesized IκBα then re-inhibits NFκB and, thus, forms an auto feedback loop, which results in oscillating levels of NFκB activity. Activation of the NFκB inducing kinase transforms a precursor protein p100 into mature p52 subunit in an IKK1/IKKa dependent manner. Then p52 dimerizes with RelB to appear as a nuclear RelB:p52 DNA binding activity and regulate a distinct class of genes. In contrast to the canonical signaling that relies upon NEMO-IKK2 mediated degradation of IκBα, β, ε, the non-canonical signaling critically depends on NFκB inducing kinase mediated processing of p100 into p52. Synthesis of the constituents of the non-canonical pathway, viz RelB and p52, is controlled by the canonical IKK2-IκB-RelA:p50 signaling. Stimuli, such as LT-α, BAFF or RANKL, activate the NFκB pathway to induce NFκB/RelB:p52 dimer in the nucleus.(1)
NF-κB is a central signaling factor involved in the development and progression of human cancers as well as in the acquisition of drug-resistant phenotype in highly aggressive malignancies. Many different types of human tumors have constitutively active NFκB, blocking apoptosis.(1) NFκB regulates anti-apoptotic genes especially the TRAF1 and TRAF2, and, therefore, checks the activities of the caspase family of enzymes.(1, 6) In tumor cells, NF-κB is active either due to mutations NFκB transcription factors or in regulators of NFκB, such as IκB. Some tumor cells also secrete NFκB activing factors. Blocking NFκB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents.(1, 7) There is evidence to support a crosstalk between PI3K/Akt/mTOR signaling pathway and NFκB.(8) IFRD1 is an inhibitor of NFκB activity, which inhibits by enhancing the HDAC-mediated deacetylation of the p65 subunit, by favoring the recruitment of HDAC3 to p65.(1)
Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents.(1, 7) However, caution should be exercised when considering anti-NFκB activity as a broad therapeutic strategy in cancer therapy. NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence. Canonical NFκB is a Fas transcription activator and the alternative NFκB is a Fas transcription repressor. Therefore, NFκB promotes Fas-mediated apoptosis in cancer cells, and thus inhibition of NFκB may suppress Fas-mediated apoptosis to impair host immune cell-mediated tumor suppression. The discovery that activation of NFκB nuclear translocation can be separated from the elevation of oxidant stress gives an important hint to the development of strategies for NFκB inhibition.(1)

Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
quinacrine, mepacrine Atabrine Incuron P2: RCC (withdrawn), PC, CRC; P1/2: NSCLC trials
TL118 Hamsa-1 Tiltan P2: pancreatic, PC trials
Minnelide 001 Minneamrita P1: GIST trials
OKN-007 NXY-059 noncorporate P1: glioma trials
SCB01A SynCore P1: solid trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
bardoxolone RTA 402 Kyowa Hakko Kirin, Abbott No ongoing trials in oncology; PIII in kidney disease due to cardiac safety; P2: melanoma; P1/2: pancreatic; P1: solid, lymphoma trials
SSR97225 Sanofi terminated; P2: various trials
teglarinad GMX1777 EB1627 Gemin X terminated; P1/2: melanoma; P1: solid, lymphoma trials

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1. NFkB. [cited]; Available from:

2. Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner E, Mueller-Dieckmann C, et al. Tyrosine phosphorylation of I?B-? activates NF-?B without proteolytic degradation of I?B-?. Cell. 1996;86(5):787-98.

3. Gilmore TD. Introduction to NF-?B: players, pathways, perspectives. Oncogene. 2006;25(51):6680-4.

4. Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D. NF-?B functions in synaptic signaling and behavior. Nature neuroscience. 2003;6(10):1072-8.

5. Pearlstein DP, Ali MH, Mungai PT, Hynes KL, Gewertz BL, Schumacker PT. Role of mitochondrial oxidant generation in endothelial cell responses to hypoxia. Arteriosclerosis, thrombosis, and vascular biology. 2002;22(4):566-73.

6. Sheikh MS, Huang Y. Death receptor activation complexes. Cell Cycle. 2003;2(6):550-2.

7. Karin M. Nuclear factor-?B in cancer development and progression. Nature. 2006;441(7092):431-6.

8. Ahmad A, Biersack B, Li Y, Kong D, Bao B, Schobert R, et al. Targeted regulation of PI3K/Akt/mTOR/NF-?B signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anti-cancer agents in medicinal chemistry. 2013;13(7):1002.

Friday, September 16, 2016 4:27 PM|Yansong Bian, Jiawei Han, Vishnu Kannabiran, Suresh Mohan, Hui Cheng, Jay Friedman, Luo Zhang, Carter VanWaes, Zhong Chen|International Journal of Biological Sciences|Labels: MEK, NFKb, HNN

The serine-threonine kinase CK2 exhibits genomic alterations and aberrant overexpression in human head and neck squamous cell carcinomas (HNSCC). Here, we investigated the effects of CK2 inhibitor CX-4945 in human HNSCC cell lines and xenograft models. The IC50's of CX-4945 for 9 UM-SCC cell lines measured by MTT assay ranged from 3.4-11.9 μM. CX-4945 induced cell cycle arrest and cell death measured by DNA flow cytometry, and inhibited prosurvival mediators phospho-AKT and p-S6 in UM-SCC1 and UM-SCC46 cells. CX-4945 decreased NF-κB and Bcl-XL reporter gene activities in both cell lines, but upregulated proapoptotic TP53 and p21 reporter activities, and induced phospho-ERK, AP-1, and IL-8 activity in UM-SCC1 cells. CX-4945 exhibited modest anti-tumor activity in UM-SCC1 xenografts. Tumor immunostaining revealed significant inhibition of PI3K-Akt-mTOR pathway and increased apoptosis marker TUNEL, but also induced p-ERK, c-JUN, JUNB, FOSL1 and proliferation (Ki67) markers, as a possible resistance mechanism. To overcome the drug resistance, we tested MEK inhibitor PD-0325901 (PD-901), which inhibited ERK-AP-1 activation alone and in combination with CX-4945. PD-901 alone displayed significant anti-tumor effects in vivo, and the combination of PD-901 and CX-4945 slightly enhanced anti-tumor activity when compared with PD-901 alone. Immunostaining of tumor specimens after treatment revealed inhibition of p-AKT S129 and p-AKT T308 by CX-4945, and inhibition of p-ERK T202/204 and AP-1 family member FOSL-1 by PD-901. Our study reveals a drug resistance mechanism mediated by the MEK-ERK-AP-1 pathway in HNSCC. MEK inhibitor PD-0325901 is active in HNSCC resistant to CX-4945, meriting further clinical investigation.

Friday, September 16, 2016 4:27 PM|Haijun Yu, Chengyue Guo, Bing Feng, Jianping Liu, Xianzhi Chen, Dangge Wang, Lesheng Teng, Youxin Li, Qi Yin, Zhiwen Zhang, Yaping Li|Theranostics|Labels: NFKb, breast cancer

The combination of chemotherapy and RNA interference is a promising approach for efficient cancer therapy. However, the success of such a strategy is hampered by the lack of suitable vectors to coordinate small interfering RNA (siRNA) and chemotherapeutic drug into one single platform. We herein report a novel triple-layered pH-responsive micelleplex loading siRNA and alkylated cisplatin prodrug for NF-Kappa B targeted treatment of metastatic breast cancer. The micelles were self-assembled from poly(ethylene glycol)-block-poly(aminolated glycidyl methacrylate)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-b-PAGA-b-PDPA) triblock copolymers. At pH 7.4, the cisplatin prodrug was encapsulated in the hydrophobic PDPA core and siRNA was loaded on the positively charged PAGA interlayer to form the micelleplexes. The PEG corona can prevent protein absorption during blood circulation, minimize non-specific interaction with the reticuloendothelial system, and prolong the systemic circulation of the micelleplexes. The positively charged PAGA interlayer can facilitate deep tumor penetration of the micelleplexes, which, upon cellular uptake, are dissociated in the early endosomes to release anticancer drug payload due to protonation of the PDPA core. Using a 4T1 breast cancer model, we demonstrate that this novel micelleplex co-loaded with cisplatin prodrug and siRNA-p65 is able to simultaneously inhibit tumor growth and suppress distant metastasis of the cancer cells by downregulating NF-kappa B expression. The results reported in this study suggest that siRNA and anticancer drug co-delivery using pH-responsive micelleplexes is a promising strategy for efficient treatment of metastatic cancer.

Background and Aim: Lipopolysaccharide(LPS) could promote the progression of colorectal cancer, but the specific regulatory mechanisms are largely unknown. So, this study aim to clarify the mechanisms that LPS upregulated VEGFR-3, which promotes colorectal cancer cells migration and invasion with a mechanism of increased NF-#x03BA;B bind to the promoter of VEGFR-3. Methods: The present study examined the VEGFR-3 expression in colorectal cancer tissues and analyzed the relationship between the VEGFR-3 expression with clinical parameters. PCR, Western blot, CCK-8, colone formation assay, and Transwell assay detected that LPS promoted the migration and invasion and the role of VEGFR-3 in the process of colorectal carcinoma in vitro. Used the methods of promoter analysis, EMSA assay and ChIP assay to explore the mechanisms LPS increased the expression of VEGFR-3. Results: VEGFR-3 was significantly high expression in the colorectal cancer tissues. And the high expression was associated with the TNM stage and lymph node metastasis of colorectal cancer. LPS could promote the migration and invasion, which could be blocked by the neutralizing antibody IgG of VEGFR-3. And found that -159 nt to +65 nt was the crucial region of VEGFR-3 promoter. And detected that the NF-#x03BA;B was important transcription factor for the VEGFR-3 promoter. And LPS could increase NF-#x03BA;B binding to VEGFR-3 promoter and upregulated the expression of VEGFR-3 to exert biological functions. Conclusion: We have elucidated the relationship between LPS and the VEGFR-3 expression and revealed that VEGFR-3 play very important role in the process of LPS promoting the migration and invasion of colorectal cancer cells. Further illuminated the mechanism that LPS upregulated VEGFR-3 expression via increased NF-#x03BA;B bind to the promoter of VEGFR-3.
Cell Physiol Biochem 2016;39:1665-1678
Contributors : Minchul Kim ; Falong Lu ; Yi Zhang
Series Type : Expression profiling by high throughput sequencing ; Genome binding/occupancy profiling by high throughput sequencing
Organism : Homo sapiens

ARID1A is frequently mutated in ovarian clear-cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here we established an in vitro model of OCCC by introducing ARID1A knock-down and mutant PIK3CA in a normal human ovarian epithelial cell line, which resulted in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while PIK3CA mutation releases RelA from IkB, leading to cytokine gene activation. We show that an NF-kB inhibitor partly attenuates proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC, and suggests NF-kB inhibition can be a potential therapeutic option.

Wednesday, September 14, 2016 5:53 PM|Wei-Tian Wei, Hui Chen, Zhao-Hong Wang, Zhong-Lin Ni, Hai-Bin Liu, Hong-Fei Tong, Hong-Chun Guo, Dian-Lei Liu, Sheng-Zhang Lin|International Journal of Biological Sciences|Labels: AKT, NFKb, PI3K, pancreatic cancer

Evodiamine has therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and evodiamine enhanced antitumor efficacy in pancreatic cancer. In vitro application of the combination therapy triggered significantly higher frequency of pancreatic cancer cells apoptosis, inhibited the activities of PI3K, Akt, PKA, mTOR and PTEN, and decreased the activation of NF-κB and expression of NF-κB-regulated products. In vivo application of the combination therapy induced significant enhancement of tumor cell apoptosis, reductions in tumor volume, and inhibited activation of mTOR and PTEN. In conclusion, evodiamine can augment the therapeutic effect of gemcitabine in pancreatic cancer through direct or indirect negative regulation of the PI3K/Akt pathway.

Tuesday, September 13, 2016 11:38 PM|Wei Huang, Quan Zhou, Xia Yuan, Ze-mei Ge, Fu-xiang Ran, Hua-yu Yang, Guang-liang Qiang, Run-tao Li, Jing-rong Cui|Journal of Cancer|Labels: Bcl-2, NFKb, STAT, ovarian cancer

Cisplatin is one of the most common drugs used for treatment of solid tumors such as ovarian cancer. Unfortunately, the development of resistance against this cytotoxic agent limits its clinical use. Here we report that YSY01A, a novel proteasome inhibitor, is capable of suppressing survival of cisplatin-resistant ovarian cancer cells by inducing apoptosis. And YSY01A treatment enhances the cytotoxicity of cisplatin in drug-resistant ovarian cancer cells. Specifically, YSY01A abrogates regulatory proteins important for cell proliferation and anti-apoptosis including NF-κB p65 and STAT3, resulting in down-regulation of Bcl-2. A dramatic increase in cisplatin uptake was also observed by inductively coupled plasma-mass spectrometry following exposure to YSY01A. Taken together, YSY01A serves as a potential candidate for further development as anticancer therapeutics targeting the proteasome.

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.

Contributors : Long Zhang ; Sen Y Zheng
Series Type : Expression profiling by high throughput sequencing
Organism : Mus musculus

The clearance of oxidative stress compounds is critical for the protection of the organism from malignancy, but how this key physiological process is regulated is not fully understood. Here we found that the expression of GPRC5A, a well-characterized tumor suppressor in lung cancer, was elevated in colorectal cancer tissues in patients. In both cancer cell lines and a colitis-associated cancer model in mice, we found that GPRC5A deficiency reduced cell proliferation and increased cell apoptosis as well as inhibited tumorigenesis in vivo. Through RNA-Seq transcriptome analysis, we identified oxidative stress associated pathways were dysregulated. Moreover, in GPRC5A deficient cells and mouse tissues, the oxidative agents were reduced partially due to increased glutathione (GSH) level. Mechanistically, GPRC5A regulates NF-κB mediated Vanin-1 expression which is the predominant enzyme for cysteamine synthesis. Administration of cystamine (the disulfide form of cysteamine) in GPRC5A deficient cell lines inhibited γ-GCS activity leading to restoration of GSH level and increase of cell growth. Taken together, our studies suggest that GPRC5a is a potential biomarker for colon cancer and promotes tumorigenesis through stimulation of Vanin-1 expression and oxidative stress in colitis associated cancer. This study revealed an unexpected oncogenic role of GPRC5A in colorectal cancer suggesting there are complicated functional and molecular mechanism differences of this gene in distinct tissues.

Monday, September 12, 2016 12:52 PM|Agerstam, H., Hansen, N., von Palffy, S., Sanden, C., Reckzeh, K., Karlsson, C., Lilljebjorn, H., Landberg, N., Askmyr, M., Hogberg, C., Rissler, M., Porkka, K., Wadenvik, H., Mustjoki, S., Richter, J., Jaras, M., Fioretos, T.|BLOOD First Edition Papers|Labels: NFKb, CML, IL

Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. IL1RAP (IL1R3) is a co-receptor of IL1R1 and has been found upregulated on CML stem cells. Here we show that primitive (CD34+CD38-) CML cells, in contrast to corresponding normal cells, express a functional IL1 receptor complex and respond with NFKB activation and marked proliferation in response to IL1. IL1RAP antibodies that inhibit IL1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rational for the development of an IL1RAP antibody therapy to target residual CML stem cells.

Wednesday, August 31, 2016 10:05 PM|C. M.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: NFKb

NF-{kappa}B in Cancer Therapeutics
Zeligs, K. P Neuman, M. K, Annunziata, C. M.
Clinical Cancer Research, Vol. 22, No. 17 (2016) pp. 4302 - 4308
The NF-B signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-B can occur as part of the DNA damage response or in response to a large variety of activators, including viruses, inflammation, and cell death. NF-B transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-B signaling is key to immune function and is likely necessary for antitumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-B. There is growing interest in identifying novel modulators to inhibit NF-B activity as impeding different steps of the NF-B pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this antiapoptotic signaling pathway to maintain antitumor immune surveillance when applying such therapy to patients. Clin Cancer Res; 22(17); 4302–8. ©2016 AACR.

Monday, August 22, 2016 6:00 PM|Ilianna Zoi, Michalis V. Karamouzis, Christos Adamopoulos, Athanasios G. Papavassiliou|Trends in Molecular Medicine|Labels: EGFR, NFKb, breast cancer
ErbB family members, ErbB1/EGFR/HER-1, ErbB2/HER-2, ErbB3/HER-3 and ErbB4/HER-4, have been implicated in breast cancer (BC) tumorigenicity. Recently, crucial roles for RANK/RANKL signaling in addition to key downstream factor NF-κB have been demonstrated in mammary tumorigenesis. Here, we present the hypothesis of a novel association between ErbB and RANK pathways in promoting BC. The proposed model alludes to the cross-talk that might occur between RANK and ErbB receptors. This interplay might regulate RANK signaling and consequently, modulate carcinogenesis, mainly in ErbB2 over-expressing BC cells.
Monday, August 22, 2016 8:40 AM|Zeligs, K. P., Neuman, M. K., Annunziata, C. M.|Clinical Cancer Research Online First Articles|Labels: NFKb

The NF-B signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-B can occur as part of the DNA damage response or in response to a large variety of activators, including viruses, inflammation, and cell death. NF-B transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-B signaling is key to immune function and is likely necessary for antitumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-B. There is growing interest in identifying novel modulators to inhibit NF-B activity as impeding different steps of the NF-B pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this antiapoptotic signaling pathway to maintain antitumor immune surveillance when applying such therapy to patients. Clin Cancer Res; 22(17); 1–7. ©2016 AACR.

Sunday, August 14, 2016 10:05 PM|Tominaga, K., Gotoh, N.|Clinical Cancer Research recent issues|Labels: AKT, IGFR, NFKb, breast cancer

An inflammatory microenvironment contributes to tumorigenesis. The pro-inflammatory transcription factor nuclear factor-kappa B (NF-kappa B) is known to play important roles, but how it regulates cancer stem cells (CSCs) remains largely unclear. We comprehensively analyzed which targets of NF-kappa B are activated by heregulin (HRG), a tumor sphere-forming ligand, in breast cancer cells. We identified many cytokines downstream of HRG-phosphatidyl inositol 3 kinase (PI3K)-NF-kappa B signaling. Insulin-like growth factor 2 (IGF2) was identified as a key downstream target; IGF2 treatment induced tumor spheres in most samples of patient-derived primary breast cancer cells, and anti-IGF2 antibody treatment greatly reduced HRG-induced tumor sphere formation, even though many other cytokines were simultaneously produced. The IGF2 receptor, IGF-1R, was specifically expressed at high levels in CSC-enriched populations in freshly obtained primary breast cancer cells. Moreover, IGF2-PI3K signaling induced expression of a stemness transcription factor, ID1, and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft (PDX) model. Thus, NF-kappa B may trigger IGF2-ID1-IGF2 positive feedback circuits and PI3K-mediated feed-forward circuits that allow cancer stem-like cells to appear; it may then stabilize the feedback circuits, to which the cancer stem-like cells become addicted. Because the stemness circuits may be the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.

Citation Format: Kana Tominaga, Noriko Gotoh. Addiction to the NF-B–triggered IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. [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 A27.

Monday, August 1, 2016 6:00 PM|Xue Xiao, Gong Yang, Peng Bai, Shunping Gui, Tri M. Bui Nyuyen, Imelda Mercado-Uribe, Mei Yang, Juan Zou, Qintong Li, Jianguo Xiao, Bin Chang, Guangzhi Liu, He Wang and Jinsong Liu|Articles: MD Anderson Cancer Center|Labels: NFKb, ovarian cancer
NF-kB can function as an oncogene or tumor suppressor depending on cancer types. The role of NF-kB in low-grade serous ovarian cancer, however, has never been tested. We sought to elucidate the function of NF-...
Sunday, July 31, 2016 10:05 PM|Eso, Y., Takai, A., Matsumoto, T., Inuzuka, T., Horie, T., Ono, K., Uemoto, S., Lee, K., Edelmann, W., Chiba, T., Marusawa, H.|Cancer Research recent issues|Labels: NFKb, liver cancer
Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB–dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2−/−AID+, ALB-MSH2−/−, and ALB-AID+ mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes. The mutation signatures in the tumors developed in these models, especially ALB-MSH2−/−AID+ mice, closely resembled those of human hepatocellular carcinoma. Our findings demonstrated that inflammation-mediated dysregulation of MSH2 may be a mechanism of genetic alterations during hepatocarcinogenesis. Cancer Res; 76(15); 4383–93. ©2016 AACR.
Thursday, July 28, 2016 7:56 AM|Haderk, F., Cid, L. L., Moussay, E., Paggetti, J., Willmund, K., Seiler, J., Diederichs, S., Goebel, M., Duerig, J., Zenz, T., Stilgenbauer, S., Zapatka, M., Lichter, P., Seiffert, M.|Cancer Research recent issues|Labels: NFKb, CLL
The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Extracellular vesicles (EV) released by CLL cells are taken up by non-malignant cells in the microenvironment and mediate major disease-related changes in recipient cells. In the current study, we characterized CLL EVs, especially focusing on vesicle-incorporated RNA transcripts, and defined the role of CLL EVs in changing the myeloid tumor microenvironment.EVs were isolated from blood plasma of CLL patients and healthy donors as well as from supernatant of the CLL cell line MEC-1 by a serial centrifugation protocol. Characterization of EVs by electron microscopy, Nanoparticle Tracking Analysis (NTA) and Western blotting revealed vesicles 30 to 350 nm in size, which are positive for various EV marker proteins such as Rab5a and Hsp70. Quantification of blood plasma-derived EVs indicated an enrichment of B-cell derived EVs in plasma of CLL patients compared to healthy donors, although absolute EV counts were not altered in CLL. Focusing on RNA analysis, an enrichment of small RNAs in EVs was observed. Subsequent small RNA sequencing revealed a unique microRNA signature of MEC-1 EVs, with CLL-relevant miRNAs such as miR-21, miR-155 and miR-146a being the most abundant miRNAs. Moreover, full length and 5'end fragment forms of Y RNAs, another class of small non-coding RNAs, were enriched in MEC-1 EVs and CLL plasma EVs. Further evaluating the functional relevance of CLL EVs within the tumor microenvironment, a rapid uptake of CLL cell-derived EVs by human monocytes and macrophages was observed. Uptake of CLL EVs in monocytes induced NFkB signaling and the release of multiple pro-inflammatory cytokines such as CCL2, CCL3, IL-6 and IL-8, which are also upregulated in plasma of CLL patients.In conclusion, tumor-derived EVs harbor a distinct set of non-coding RNAs. The uptake of EVs in recipient cells and the concomitant transfer of incorporated RNAs mediate substantial phenotypic changes in target cells. In the current study, this is exemplified for monocytes, which present several disease-relevant alterations upon EV uptake, including cellular activation and secretion of pro-inflammatory cytokines.Citation Format: Franziska Haderk, Laura Llao Cid, Etienne Moussay, Jerome Paggetti, Karolin Willmund, Jana Seiler, Sven Diederichs, Maria Goebel, Jan Duerig, Thorsten Zenz, Stephan Stilgenbauer, Marc Zapatka, Peter Lichter, Martina Seiffert. Chronic lymphocytic leukemia-derived extracellular vesicles mediate NFkB signaling and pro-inflammatory cytokine release in monocytes. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A30.
Monday, June 27, 2016 10:52 AM|PYLVAS-EEROLA, M., LIAKKA, A., PUISTOLA, U., KOIVUNEN, J., KARIHTALA, P.|Anticancer Research recent issues|Labels: NFKb, ovarian cancer

Background/Aim: The nuclear factor erytheroid 2–related factor 2-kelch-like ECH-associated protein (NRF2-KEAP1) system and stem cell-like cancer cells are associated with platinum resistance in ovarian cancer. Our objective was to investigate the possible association between platinum resistance, cellular redox-state regulation and stem cell properties in ovarian cancer. Patients and Methods: Thirty-eight patients with epithelial ovarian cancer were included. All patients had undergone primary diagnostic laparoscopy, platinum-based neoadjuvant chemotherapy, and debulking surgery. Tumor samples were analyzed for NRF2, KEAP1, protein deglycase 1 (DJ1/PARK7), cluster of differentiation molecules 44 (CD44) and 117 (CD117) and aldehyde dehydrogenase 1 (ALDH1) by immunohistochemistry. Results: Positive pre-treatment expression of CD44 (p=0.013) and stable/increased post-therapy CD44 expression were associated with platinum resistance (p=0.001). Negative pre-treatment expression of cytoplasmic ALDH1 predicted sensitivity to platinum (p=0.017). Pre-treatment nuclear KEAP1 expression was greater in stage II-III cancer (p=0.0003). After neoadjuvant treatment, all samples were nuclear KEAP1-positive (p=0.025) and increased nuclear KEAP1 expression was associated with higher tumor stage (p=0.0001). Conclusion: CD44 and cytoplasmic ALHD1 could be potential indicators of platinum resistance during neoadjuvant chemotherapy for ovarian cancer.

Monday, June 13, 2016 8:46 AM|Guo, X., Zheng, L., Jiang, J., Zhao, Y., Wang, X., Shen, M., Zhu, F., Tian, R., Shi, h., Xu, M., Li, X., Peng, F., Zhang, H., Feng, Y., Xie, Y., Xu, X., Jia, W., He, R., Xie, C., Hu, J., Ye, D., Wang, M., Qin, R.|Clinical Cancer Research Online First Articles|Labels: NFKb, pancreatic cancer

Purpose:We sought to find new immune-based treatments for pancreatic cancer (PC). Experimental Design: We detected interleukin (IL)-18 expression in plasma and specimens from patients with PC. We then investigated whether IL-18 had a therapeutic effect for PC in vitro and in vivo, and any underlying mechanisms. Results: Higher plasma IL-18 was associated with longer overall survival, but higher IL-18 in PC tissues was associated with shorter overall survival and increased invasion and metastasis. Recombinant IL-18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral bloods and lymph nodes. However, IL-18 promoted the proliferation and invasion of PC cells, in vitro and in vivo, through the NF-B pathway. Nevertheless, by co-administrating IL-18 with BAY11-7082, a NF-B inhibitor, we were able to prevent the pro-cancerous effects of IL-18 and prolong the survive time of the mice. Conclusions: IL-18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on PC, when combined with the NF-B pathway inhibitor, IL-18 improved survival in a murine PC model. Our study implies the possibility of a combinational immunotherapy that uses IL-18 and targets NF-B pathway.

Wednesday, June 8, 2016 3:00 PM|Current Pharmaceutical Design|Current Pharmaceutical Design via|Comments|Labels: NFKb
CONCLUSION: Both basic and clinical research revealed that constitutive activation of NF-κB is the prime reason for inducing drug resistance in cancer cells. This comprehensive review scientifically evaluates the chemo sensitizing potential of these natural agents which serve as potent NF-κB blockers, based on evidence based literature. PMID: 27291284 [PubMed - as supplied by publisher] (Source: Current Pharmaceutical Design)
Thursday, April 28, 2016 9:59 AM|DA COSTA, R. M. G., BASTOS, M. M. S. M., MEDEIROS, R., OLIVEIRA, P. A.|Anticancer Research recent issues|Labels: NFKb, cervical cancer

Papillomaviruses induce a range of benign and malignant lesions in their hosts, including cervical cancer, that is associated with high-risk human papillomavirus (HPV) types. The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFB) plays a pivotal role in HPV-infected cells, and its expression and activity are modulated by several viral oncoproteins. NFB modulation seems to first facilitate viral persistence and immune evasion, and later to drive tumour progression, but the many conflicting results and the complexity of its signaling networks require great prudence while interpreting the role of NFB in papillomaviral lesions. Accordingly, the pharmacological targeting of the NFB pathway in HPV-induced lesions is a complex and currently unmet challenge. This review deals with recent findings concerning NFB activation in HPV-infected cells, its role in viral persistence, cell transformation and tumour progression, and with current efforts to target this pathway for cancer prevention and therapy.

Monday, March 21, 2016 4:00 PM|Matrix Biology|MedWorm: Cancer Therapy|Comments|Labels: HPSE, NFKb, MM
Authors: Ramani VC, Vlodavsky I, Ng M, Zhang Y, Barbieri P, Noseda A, Sanderson RD Abstract High heparanase expression is associated with enhanced tumor growth, angiogenesis, and metastasis in many types of cancer. However, the mechanisms driving high heparanase expression are not fully understood. In the present study, we discovered that drugs used in the treatment of myeloma upregulate heparanase expression. Frontline anti-myeloma drugs, bortezomib and carfilzomib activate the nuclear factor-kappa B (NF-κB) pathway to trigger heparanase expression in tumor cells. Blocking the NF-κB pathway diminished this chemotherapy-induced upregulation of heparanase expression. Activated NF-κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines....
Sunday, February 28, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: NFKb, breast cancer
In this study, we investigated miRNA-mediated regulation of the NF-κB cascade in breast cancer. We report that miR-892b expression was significantly downregulated in human breast cancer specimens and correlated with poor patient survival. Overexpression of miR-892b in breast cancer cells significantly decreased tumor growth, metastatic capacity, and the ability to induce angiogenesis, whereas miR-892b depletion enhanced these properties, in vitro and in vivo. Furthermore, we demonstrate that miR-892b attenuated NF-κB signaling by directly targeting and suppressing multiple mediators of NF-κB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-κB activity. Moreover, miR-892b downregulation was attributed to aberrant hypermethylation of its p...

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