The Role of C-SRC Activation in Prostate Tumor Progression
Final rept. 1 Jul 2003-30 Jun 2006
M D ANDERSON CANCER CENTER HOUSTON TX
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DOD Award number DAMD17-03-1-0484, The Role of c-Src Activation in Prostate Tumor Progression, had as its goal an understanding of how activation of the protein tyrosine kinase, Src, contributes to prostate tumor progression. During the award period, we demonstrated that Src activation directly contributes to the development of lymph node metastases by increasing the expression of vascular endothelial growth factor VEGF. We demonstrated that Src must be activated i.e. increased in specific activity of its kinase as overexpression of wild type Src did not increase lymph node metastasis nor did it increase VEGF expression. Using a system in which activated Src could be induced, we demonstrated that phosphorylation of the Src substrate and transcription factor, STAT3, led to a complex on the VEGF promoter that directly increased transcription of VEGF, thus identifying the mechanism by which activated Src increases expression of this critical angiogenic factor. In the second task, we demonstrated that Src activation confers resistance to apoptosis in prostate cancer cells. In the final task, we developed Src-- nude mice, which will be useful in testing the role of Src in hosttumor interactions. The results of these studies suggest that Src will be an important therapeutic target for prostate cancer therapy, and clinical trials on Src inhibitors for this purpose will begin in 2006.
- Medicine and Medical Research