BACKGROUND The Src tyrosine kinase substrate and adaptor protein Tks5 had previously been implicated in the invasive phenotype of normal and transformed cell types via regulation of cytoskeletal structures called podosomes/invadopodia. The role of Src-Tks5 signaling in invasive prostate cancer, however, had not been previously evaluated. METHODS We measured the relative expression of Tks5 in normal (n = 20) and cancerous (n = 184, from 92 patients) prostate tissue specimens by immunohistochemistry using a commercially available tumor microarray. We also manipulated the expression and activity of wild-type and mutant Src and Tks5 constructs in the LNCaP and PC-3 prostate cancer cell lines in order to ascertain the role of Src-Tks5 signaling in invadopodia development, matrix-remodeling activity, motility, and invasion. RESULTS Our studies demonstrated that Src was activated and Tks5 upregulated in high Gleason score prostate tumor specimens and in invasive prostate cancer cell lines. Remarkably, overexpression of Tks5 in LNCaP cells was sufficient to induce invadopodia formation and associated matrix degradation. This Tks5-dependent increase in invasive behavior further depended on Src tyrosine kinase activity and the phosphorylation of Tks5 at tyrosine residues 557 and 619. In PC-3 cells we demonstrated that Tks5 phosphorylation at these sites was necessary and sufficient for invadopodia-associated matrix degradation and invasion. CONCLUSIONS Our results suggest a general role for Src-Tks5 signaling in prostate tumor progression and the utility of Tks5 as a marker protein for the staging of this disease.
Much of the morbidity and mortality in prostate cancer patients occurs strictly in response to metastatic disease. While ongoing efforts are examining the therapeutic value of Src kinase inhibitors, the mechanism by which Src activates invasive cell behavior within the context of this disease are not well-understood. Invadopodia are cytoskeletal structures formed by cancer cells that enable binding to, proteolytic degradation of, and invasion through the extracellular matrix. We and others have previously demonstrated that the Src tyrosine kinase substrate and adaptor protein Tks5 is important for invadopodia formation and function. Here we demonstrate that Src is activated and Tks5 up-regulated in prostate tumor specimens and invasive cell lines. Remarkably, overexpression of Tks5 alone is sufficient to form invadopodia structures and enhance invadopodia-associated gelatin degradation and invasion in the LNCaP cell line. We further show that this increase in invasive behavior likely depends on Src kinase activity and Tks5 phosphorylation. Our results predict a role for Src-Tks5 signaling in prostate tumor progression. This hypothesis will be tested in future studies using (i) mouse xenografts to monitor tumor development from Tks5-modified prostate cancer cell lines, and (ii) human prostate tumor tissue sections to measure Tks5 staining relative to tumor grade. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 503. doi:1538-7445.AM2012-503
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