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SRC
SRC
SRC(3)

Proto-oncogene tyrosine-protein kinase Src, a non-receptor PTK protein encoded by the SRC gene, and belongs to a family of non-RTKs called SFKs.(605) c-Src should not be confused with cellular Src kinase or C-terminal Src kinase (CSK), an enzyme which phosphorylates c-Src at its C-terminus and provides negative regulation of Src's enzymatic activity. Src promotes survival, angiogenesis, proliferation, and invasion pathways. There are 9 members part of the SFKs: c-Src, Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck, and Lck. Src, Fyn, and Yes are expressed ubiquitously in all cell types while the other members of SFKs are generally found in hematopoietic cells.(1) c-Src includes an SH2 domain, an SH3 domain, and a TYK domain.(1)
c-Src can be activated by many transmembrane proteins that include: adhesion receptors, RTKs, G-protein coupled receptors and cytokine receptors. Most studies have looked at the RTKs and examples of these are PDGFR pathway and EGFR. EGFR activates c-Src while EGF also increases the activity of c-Src.(1, 2) Src (gene) has been shown to interact with the following signaling pathways: Lyn is a protein encoded in humans by the LYN gene.(3) Lyn has an inhibitory role in myeloid lineage proliferation.(4) In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the BCR, CD40, or CD19. The abbreviation Lyn is derived from Lck/Yes novel TYK, Lck and Yes also being members of the Src kinase family.(3) Following engagement of the BCRs, Lyn undergoes rapid phosphorylation and activation. LYN activation triggers a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk and PI3K.(5) Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, and PIR-B. In B-cells, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition.(3, 6) Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates IR substrate 1 (IRS1).(3) LYN has been shown to interact with a number of other proteins, including: CD117, CD22, Cdk1, MUC1, and NEDD9.(3, 7-9)
The activation of the c-Src pathway has been observed in about 50% of CRC, HCC, lung, BC, and pancreatic cancers.(10) At one point an ancestral virus may have mistakenly incorporated the c-Src gene of its cellular host. Eventually this normal gene mutated into an abnormally functioning oncogene within the Rous sarcoma virus.(1) Elevated c-Src levels have also been shown to have a correlation with advances stages of the tumor, size of tumor, and metastatic potential of tumors.(1, 11) Members of the SFKs, Src, Lyn and Fgr are highly expressed in PC.(1)

Drugs/Indications
Marketed Drugs
Generic Code Old Code Brand Company Indication trials
bosutinib PF-05208763 SKI-606 Bosulif Pfizer Mkt: CML; P2: BC, GBM; P1/2: ALL, pancreatic; P1: solid trials
dasatinib, desatinib BMS-354825 Sprycel BMS Mkt: CML, ALL; P3: PC; P2: pancreatic, BC, CLL, MDS, NSCLC, fallopian, HNN, endometrial, lymphoma, neuroblastoma, GIST, SCLC, melanoma, rhabdomysarcoma; P1/2: GBM, NHL, brain, CNS; P1: CRC, mesothelioma, MM, solid, ovarian, peritoneal trials
ponatinib AP24534 Iclusig Ariad Mkt: CML, ALL; P2/3: NSCLC, HNN; P2: GIST, thyroid, HCC, SCLC trials
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
tesevatinib XL647 KD019 Kardom, Exelixis P3: NSCLC (terminated); P2: BC, brain mets; P1: solid, esophageal (2014), stomach (2014), BC (2015) trials
saracatinib AZD0530 AstraZeneca P2/3: ovarian, fallopian, peritoneal; P2: osteosarcoma, pancreatic, NSCLC, gastroesophageal, BC, PC, HNN, CRC (terminated), thyroid, bibrosarcoma, leiomyosarcoma; P1: solid trials
bafetinib NS-187 INNO-406 CytRx P2: PC, CLL trials
KX2-391 Hanmi P2: PC; P1/2: solid; P1: AML, solid, lymphoma trials
CWP232291 JW P1: AML, CML, MDS, MF trials
SAR103168 Sanofi P1: AML trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
XL228 Exelixis terminated; P1: CML, ALL, lymphoma trials
XL999 Exelixis terminated; P2: CRC, ovarian, NSCLC, MM, RCC, AML; P1: solid trials


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References

1. Src_(gene). [cited]; Available from: http://en.wikipedia.org/wiki/Src_(gene).

2. Ottenhoff-Kalff A, Rijksen G, Van Beurden E, Hennipman A, Michels A, Staal G. Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product. CANCER RESEARCH. 1992;52(17):4773-8.

3. Lyn_(Src_family_kinase). [cited]; Available from: http://en.wikipedia.org/wiki/Lyn_(Src_family_kinase).

4. Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, et al. Gain-and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. immunity. 2001;15(4):603-15.

5. Yamanashi Y, Fukui Y, Wongsasant B, Kinoshita Y, Ichimori Y, Toyoshima K, et al. Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling. Proceedings of the National Academy of Sciences. 1992;89(3):1118-22.

6. Saijo K, Schmedt C, Su I-h, Karasuyama H, Lowell CA, Reth M, et al. Essential role of Src-family protein tyrosine kinases in NF-?B activation during B cell development. Nature immunology. 2003;4(3):274-9.

7. Sidorenko SP, Law C-L, Chandran KA, Clark EA. Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein. Proceedings of the National Academy of Sciences. 1995;92(2):359-63.

8. Pathan NI, Geahlen RL, Harrison ML. The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2. Journal of Biological Chemistry. 1996;271(44):27517-23.

9. Durum SK, Aiello FB. Interleukin-7 induces MUC1. Cancer biology & therapy. 2003;2(2):194-5.

10. Dehm SM, Bonham K. SRC gene expression in human cancer: the role of transcriptional activation. Biochemistry and cell biology. 2004;82(2):263-74.

11. Allgayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE. Activation of Src kinase in primary colorectal carcinoma. Cancer. 2002;94(2):344-51.



News
Wednesday, September 21, 2016 10:33 AM|Lonard, D. M., O'Malley, B. W.|Clinical Cancer Research Online First Articles|Labels: Src

Coactivators represent a large class of proteins that partner with nuclear receptors (NRs) and other transcription factors to regulate gene expression. Given their pleiotropic roles in the control of transcription, coactivators have been implicated in a broad range of human disease states, including cancer. This is best typified by the three members of the steroid receptor coactivator (SRC) family, each of which integrates steroid hormone signaling and growth factor pathways to drive oncogenic gene expression programs in breast, endometrial, ovarian, prostate and other cancers. Because of this, coactivators represent emerging targets for cancer therapeutics and efforts are now being made to develop SRC-targeting agents such as the SI-2 inhibitor and the novel SRC stimulator, MCB-613, that are able to block cancer growth in cell culture and animal model systems. Here, we will discuss the mechanisms through which coactivators drive cancer progression and how targeting coactivators represent a novel conceptual approach to combat tumor growth that is distinct from the use of other targeted therapeutic agents. We also will describe efforts to develop next-generation SRC inhibitors and stimulators that can be taken into the clinic for the treatment of recurrent, drug-resistant cancers.

Wednesday, September 14, 2016 10:11 PM|Jean Ching-Yi Tien, Suoling Zhou, Jianming Xu|International Journal of Biological Sciences|Labels: Src, prostate cancer

The androgen and androgen receptor (AR)-regulated gene expression plays important roles in normal prostate and prostate cancer development, and AR transcriptional control of genes is mediated by transcriptional coactivators, including the three members of the steroid receptor coactivator (SRC) family, SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2) and SRC-3 (AIB1, ACTR/RAC3/NCOA3). SRC-1 and SRC-3 are overexpressed in multiple human endocrine cancers and knockdown of either one of them in prostate cancer cell lines impedes cellular proliferation. Knockout of SRC-3 in mice suppresses the progression of spontaneous prostate carcinogenesis. In this study, we investigated SRC-1 contribution to prostate cancer in vivo by deleting the SRC-1 gene in TRAMP mice, which contain the probasin promoter-driven SV40 T/t antigen transgene. In assessing tumor mass of mice at various ages, we found that initiation and progression of prostate cancer induced by SV40 T/t antigens were unaltered in SRC-1-/- mice versus WT mice. Primary tumor histology and metastasis to distant lymph nodes were also similar in these mice at all time points assessed. These results demonstrate that the role of SRC-1 in mouse prostate carcinogenesis is nonessential and different from the essential contribution of SRC-3 that is required for prostate cancer progression and metastasis in mice. Interestingly, we observed that during prostate tumorigenesis SRC-1 expression was relatively constant, while SRC-3 expression was significantly elevated. Therefore, the loss of SRC-1 function may be compensated by SRC-3 overexpression during prostate tumorigenesis in SRC-1-/- mice.

Wednesday, September 14, 2016 5:53 PM|Claire A. Walsh, Li Qin, Jean Ching-Yi Tien, Leonie S. Young, Jianming Xu|International Journal of Biological Sciences|Labels: Src

In 1995, the steroid receptor coactivator-1 (SRC-1) was identified as the first authentic steroid receptor coactivator. Since then, the SRC proteins have remained at the epicenter of coregulator biology, molecular endocrinology and endocrine-related cancer. Cumulative works on SRC-1 have shown that it is primarily a nuclear receptor coregulator and functions to construct highly specific enzymatic protein complexes which can execute efficient and successful transcriptional activation of designated target genes. The versatile nature of SRC-1 enables it to respond to steroid dependent and steroid independent stimulation, allowing it to bind across many families of transcription factors to orchestrate and regulate complex physiological reactions. This review highlights the multiple functions of SRC-1 in the development and maintenance of normal tissue functions as well as its major role in mediating hormone receptor responsiveness. Insights from genetically manipulated mouse models and clinical data suggest SRC-1 is significantly overexpressed in many cancers, in particular, cancers of the reproductive tissues. SRC-1 has been associated with cellular proliferation and tumor growth but its major tumorigenic contributions are promotion and execution of breast cancer metastasis and mediation of resistance to endocrine therapies. The ability of SRC-1 to coordinate multiple signaling pathways makes it an important player in tumor cells' escape of targeted therapy.

Friday, September 2, 2016 6:35 AM|Gilani, R. A., Phadke, S., Bao, L. W., Lachacz, E. J., Dziubinski, M. L., Brandvold, K. R., Steffey, M. E., Kwarcinski, F. E., Graveel, C. R., Kidwell, K. M., Merajver, S. D., Soellner, M. B.|Clinical Cancer Research Online First Articles|Labels: Src, breast cancer

Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.

Experimental Design: We have analyzed the anti–triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts.

Results: We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.

Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 1–10. ©2016 AACR.

Wednesday, August 31, 2016 10:05 PM|Fournier, P., Dussault, S., Fusco, A., Rivard, A., Royal, I.|Cancer Research recent issues|Labels: Src, VEGF
The protein tyrosine phosphatase PTPRJ/DEP-1 has been implicated in negative growth regulation in endothelial cells, where its expression varies at transitions between proliferation and contact inhibition. However, in the same cells, DEP-1 has also been implicated in VEGF-dependent Src activation, permeability, and capillary formation, suggesting a positive role in regulating these functions. To resolve this dichotomy in vivo, we investigated postnatal angiogenesis and vascular permeability in a DEP-1–deficient mouse. In this study, we report that DEP-1 is required for Src activation and phosphorylation of its endothelial cell–specific substrate, VE-cadherin, after systemic injection of VEGF. Accordingly, VEGF-induced vascular leakage was abrogated in the DEP-1–deficient mice. Furthermore, capillary formation was impaired in murine aortic tissue rings or Matrigel plugs infused with VEGF. In the absence of DEP-1, angiogenesis triggered by ischemia or during tumor formation was defective, which in the latter case was associated with reduced tumor cell proliferation and increased apoptosis. Macrophage infiltration was also impaired, reflecting reduced vascular permeability in the tumors or a possible cell autonomous effect of DEP-1. Consequently, the formation of spontaneous and experimental lung metastases was strongly decreased in DEP-1–deficient mice. In clinical specimens of cancer, less vascularized tumors exhibited lower microvascular expression of DEP-1. Altogether, our results established DEP-1 as an essential driver of VEGF-dependent permeability, angiogenesis, and metastasis, suggesting a novel therapeutic route to cancer treatment. Cancer Res; 76(17); 5080–91. ©2016 AACR.
Sunday, August 14, 2016 10:05 PM|Kuo, W.-T., Lee, T.-C., Yu, L. C.-H.|Cancer Research recent issues|Labels: Src, CRC
Colorectal carcinogenesis is affected by overexpression of the lipopolysaccharide (LPS) receptors CD14 and TLR4, which antagonize each other by affecting epithelial cell proliferation and apoptosis. Eritoran is an investigational drug for sepsis treatment that resembles the lipid A moiety of LPS and therefore acts as a TLR4 inhibitor. In the present study, we explored the potential therapeutic uses and mechanisms of action of eritoran in reducing colon cancer progression. Eritoran administration via intracolonic, intragastric, or intravenous routes significantly reduced tumor burden in a chemically induced mouse model of colorectal carcinoma. Decreased proliferation and increased apoptosis were observed in mouse tumor cells after eritoran treatment. In vitro cultures of mouse primary tumor spheroids and human cancer cell lines displayed increased cell proliferation and cell-cycle progression following LPS challenge. This effect was inhibited by eritoran and by silencing CD14 or TLR4. In contrast, apoptosis induced by eritoran was eliminated by silencing CD14 or protein kinase Cζ (PKCζ) but not TLR4. Lastly, LPS and eritoran caused hyperphosphorylation of PKCζ in a CD14-dependent and TLR4-independent manner. Blocking PKCζ activation by a Src kinase inhibitor and a PKCζ-pseudosubstrate prevented eritoran-induced apoptosis. In summary, our work offers a preclinical proof of concept for the exploration of eritoran as a clinical treatment, with a mechanistic rationale to reposition this drug to improve the management of colorectal cancer. Cancer Res; 76(16); 4684–95. ©2016 AACR.
Thursday, July 28, 2016 7:56 AM|Kidambi, S.|Cancer Research recent issues|Labels: Src, breast cancer
The development of resistance to trastuzumab is a major obstacle for lasting effective treatment of patients with ErbB2-overexpressing tumors. Here, we demonstrate that the physical contact of breast cancer cells with mesenchymal stem cells (MSCs) is a potential modulator of trastuzumab response by activation of nonreceptor tyrosine kinase c-SRC (Src) and down regulation of phosphatase and tensin homolog (PTEN). In this study we demonstrate a method for controlling breast cancer cells adhesion on polyelectrolyte multilayer (PEM) films without the aid of adhesive proteins/ligands to study the role of tumor and stromal cell interaction on cancer biology. Numerous studies have explored engineering co-culture of tumor and stromal cells predominantly using transwell co-culture of stromal cells cultured onto cover slips that were subsequently added to tumor cell cultures. However, these systems imposed an artificial boundary that precluded cell-cell interactions. To our knowledge this is the first demonstration of patterned co-culture of tumor cells and stromal cells that captures the temporal changes in the miRNA signature as the breast tumor develops through various stages. In this study we utilized cancer cells derived from two different tumor stages and two different stromal cells to effectively model heterogeneous tumor microenvironment and emulate various tumor stages. The co-culture model mimics the proliferative index (Ki67 expression) and tumor aggressiveness (HER-2 expression) akin to those observed in clinical tumor samples. We also demonstrated that our patterned co-culture model captures the temporal changes in the miRNA-21 and miRNA-34 signature as the breast tumor develops through various stages. Using our patterned breast cancer/MSC co-culture model, we find that the presence of MSCs results in Src activation that is missing in cancer cells monoculture, transwell co-culture, and cells treated with MSCs conditioned media. Interestingly, the co-culture model also results in PTEN loss and activation of PI3K/AKT pathway that has been demonstrated as fundamental proliferative and survival pathways in clinical settings. In addition, breast cancer cells in co-culture with MSCs conferred trastuzumab resistance in vitro as observed in the lack of inhibition of proliferative and migrative properties of the cancer cells. Our findings show that MSCs are potent mediators of resistance to trastuzumab and might reveal targets to enhance trastuzumab efficacy in patients. The engineered co-culture platform lays groundwork towards precision medicine wherein patient-derived tumor cells can be incorporated within our in vitro models to identify potential pathways and drug treatment regimens for individual patients.Citation Format: Srivatsan Kidambi. Physical intimacy of breast cancer cells with mesenchymal stem cells elicits trastuzumab resistance through Src activation. [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 A33.
Sunday, July 17, 2016 10:05 PM|Anjanappa, M., Burnett, R., Zieger, M. A., Merfeld-Clauss, S., Wooden, W., March, K., Tholpady, S., Nakshatri, H.|Molecular Cancer Research recent issues|Labels: Src, breast cancer

Adipose-derived stem cells (ASC) have received considerable attention in oncology because of the known direct link between obesity and cancer as well as the use of ASCs in reconstructive surgery after tumor ablation. Previous studies have documented how cancer cells commandeer ASCs to support their survival by altering extracellular matrix composition and stiffness, migration, and metastasis. This study focused on delineating the effects of ASCs and adipocytes on the self-renewal of stem/progenitor cells and hierarchy of breast epithelial cells. The immortalized breast epithelial cell line MCF10A, ductal carcinoma in situ (DCIS) cell lines MCF10DCIS.com and SUM225, and MCF10A-overexpressing SRC oncogene were examined using a mammosphere assay and flow cytometry for the effects of ASCs on their self-renewal and stem-luminal progenitor-differentiated cell surface marker profiles. Interestingly, ASCs promoted the self-renewal of all cell types except SUM225. ASC coculture or treatment with ASC conditioned media altered the number of CD49fhigh/EpCAMlow basal/stem-like and CD49fmedium/EpCAMmedium luminal progenitor cells. Among multiple factors secreted by ASCs, IFN and hepatocyte growth factor (HGF) displayed unique actions on epithelial cell hierarchy. IFN increased stem/progenitor-like cells while simultaneously reducing the size of mammospheres, whereas HGF increased the size of mammospheres with an accompanying increase in luminal progenitor cells. ASCs expressed higher levels of HGF, whereas adipocytes expressed higher levels of IFN. As luminal progenitor cells are believed to be prone for transformation, IFN and HGF expression status of ASCs may influence susceptibility for developing breast cancer as well as on outcomes of autologous fat transplantation on residual/dormant tumor cells.

Implications: This study suggests that the ratio of ASCs to adipocytes influences cancer cell hierarchy, which may impact incidence and progression. Mol Cancer Res; 14(7); 660–71. ©2016 AACR.

Tuesday, May 10, 2016 8:29 AM|Mitri, Z., Nanda, R., Blackwell, K., Costelloe, C. M., Hood, I., Wei, C., Brewster, A. M., Ibrahim, N. K., Koenig, K. B., Hortobagyi, G. N., Van Poznak, C., Rimawi, M. F., Moulder-Thompson, S.|Clinical Cancer Research Online First Articles|Labels: Src, breast cancer

Purpose Osteoclast mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase 2 dose (RP2D) and clinical efficacy of the src-kinase inhibitor dasatinib combined with zoledronic acid (ZA) in bone predominant, HER2-negative breast cancer metastases. Experimental Design A 3+3 lead in phase I design confirmed the recommended phase 2 dose (RP2D) allowing activation of the single arm, phase II trial. ZA was administered IV on day 1 and dasatinib was given po once daily for 28 days each cycle as twice daily administration caused dose limiting toxicity. Response was assessed every 3 cycles. N-telopeptide (NTx) was serially measured. Results 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib=100 mg/day. Common adverse events (AEs) were grade 1-2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PRs). The clinical benefit rate (PRs + stable disease (SD) > 6 months) in bone was 8/22 (36%). Median time to treatment failure was 2.70 months (95% CI: 1.84 - 5.72) in the general cohort, 3.65 months (95% CI: 1.97 - 7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI: 0.30 - NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR positive status, and pre-treatment high NTx levels. Conclusion Combination therapy was well tolerated, and produced responses in bone in patients with HR-positive tumors.

Thursday, April 28, 2016 9:59 AM|ALHO, I., COSTA, L., BICHO, M., COELHO, C.|Anticancer Research recent issues|Labels: Src

Background/Aim: During the bone metastatic process, tumor cells and bone cells drive a vicious cycle stimulating growth and activity of each other. We here address how low molecular weight protein tyrosine phosphatase (LMW-PTP) could be involved in this process. Materials and Methods: We targeted LMW-PTP by siRNA and evaluated the effect of various soluble factors released to the culture medium by the MDA-MB-435 breast cancer cell line, in RAW 264.7 osteoclastogenesis. Results: We showed that these soluble factors did not change RAW 264.7 osteoclastogenic potential. The knockdown of the LMW-PTP slow isoform decreased osteoclastogenesis of RAW 264.7, showing less active Src. The knockdown of LMW-PTP and its slow isoform decreased the release of IL-8 but not IL-6 in MDA-MB-435. Conclusion: The LMW-PTP slow isoform can be an important protein in bone metastatic disease, with a fundamental role in the interplay between tumor cells and osteoclasts, through the regulation of Src activity and IL-8 secretion.

Saturday, March 19, 2016 10:53 AM|Oncology Reports|MedWorm: Cancer Therapy|Comments|Labels: Src, TGF, lung cancer
Authors: Da C, Liu Y, Zhan Y, Liu K, Wang R Abstract Epithelial-mesenchymal transition (EMT) is a critical cellular process in cancer metastasis, during which epithelial polarized cells become motile mesenchymal cells. Since transforming growth factor-β (TGF-β) is a potent inducer of EMT, blocking of TGF-β/Smad signaling has become a promising cancer therapy. Nobiletin, a polymethoxy flavonoid from Citrus depressa, has been shown to be valuable for cancer treatment, yet the mechanism remains unclear. In the present study, lung adenocarcinoma A549 and H1299 cells were used to evaluate the effect of nobiletin on EMT induced by TGF-β1. Nobiletin successfully inhibited TGF-β1-induced EMT, migration, invasion and adhesion in vitro, accompanied by attenuation of MMP-2, MMP-9, p-Src...
Saturday, January 30, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: Src, STAT, brain cancer, breast cancer, prostate cancer
STAT3 offers an attractive target for cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid–based and benzoic acid–based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src–transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, and survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA-binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3-inhibitory effects of ...