Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma.
ABSTRACT Src signaling has been implicated in several malignancies including melanoma. The prevalence of Src activation in human melanoma and the effect of the newer Src inhibitors, dasatinib, and bosutinib (SKI-606), as single agents or in combination, on melanoma cell lines is not well established. In the melanoma cell lines, A-375, SK-Mel-5, and SK-Mel-28, activity of Src inhibitors was assessed alone or in combination with standard chemotherapy agents; 50% growth inhibitory concentration was determined by MTS assay and immunoblotting was used to measure Src activation and downstream signaling. Staining for Src activation was measured by Src-phosphotyrosine 416. Immunohistochemistry was performed on primary cutaneous, mucosal, and metastatic melanoma. Src inhibitors blocked the growth of melanoma cell lines; furthermore, Src inhibitor treatment was synergized with cisplatin but not temozolomide or paclitaxel. Treatment with dasatanib increased the levels of pS473 Akt in A-375 melanoma cells but not in the other two cell lines. Forty-eight percent (17 of 35) of all melanoma stained weakly, moderately, or strongly for pY416 Src: cutaneous 61% (eight of 13), mucosal 31% (four of 13), metastatic 55% (five of nine). Most positive biopsies stained weakly and only one metastatic melanoma specimen stained strongly for Src-phosphotyrosine 416. pY416 Src is expressed in cutaneous, mucosal, and metastatic melanoma in various degrees. Src inhibitors may be a promising therapy in melanoma, either by themselves or in combination with chemotherapy (especially with platinum compounds) or inhibitors of the Akt/PI3k pathway.
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ABSTRACT: The TNF receptor superfamily member Fn14 (TNFRSF12A) is the sole signaling receptor for the pro-inflammatory cytokine TWEAK (TNFSF12). TWEAK:Fn14 engagement stimulates multiple signal transduction pathways, including the NF-κB pathway, and this triggers important cellular processes (e.g., growth, differentiation, migration, invasion). The TWEAK/Fn14 axis is thought to be a major physiological mediator of tissue repair after acute injury. Various studies have revealed that Fn14 is highly expressed in many solid tumor types and that Fn14 signaling may play a role in tumor growth and metastasis. Previously it was shown that Fn14 levels are frequently elevated in non-small cell lung cancer (NSCLC) tumors and cell lines that exhibit constitutive EGFR phosphorylation (activation). Furthermore, elevated Fn14 levels increased NSCLC cell invasion in vitro and lung metastatic tumor colonization in vivo. The present study reveals that EGFR-mutant NSCLC cells that express high levels of Fn14 exhibit constitutive activation of the cytoplasmic tyrosine kinase Src and that treatment with the Src family kinase (SFK) inhibitor dasatinib decreases Fn14 gene expression at both the mRNA and protein levels. Importantly, siRNA-mediated depletion of the SFK member Src in NSCLC cells also decreases Fn14 expression. Finally, expression of the constitutively active v-Src oncoprotein in NIH 3T3 cells induces Fn14 gene expression and NIH 3T3/v-Src cells require Fn14 expression for full invasive capacity. Implications: These results indicate that oncogenic Src may contribute to Fn14 overexpression in solid tumors and that Src-mediated cell invasion could potentially be inhibited with Fn14-targeted therapeutics.Molecular Cancer Research 11/2014; 13(3). DOI:10.1158/1541-7786.MCR-14-0411 · 4.50 Impact Factor
- Cancer Cell 06/2012; · 23.89 Impact Factor
- Advances in Biological Chemistry 01/2013; 03(03):6-11. DOI:10.4236/abc.2013.33A002