Abstract
Abstract Src signaling plays an important role in prostate cancer (PrCa) progression. Dasatinib, an oral src family kinase inhibitor, is being tested in patients with PrCa in several Phase II and III clinical trials. It has been shown that src interacts with androgen receptor (AR) and enhances AR transactivation. Although it has been shown that src promotes AR activity, the underlying pathway has not been defined. To characterize the src-AR pathway, we first analyzed the localization of src, AR, and Prostate Specific Antigen (PSA, an AR target gene). Using sub-cellular fractionation and immunofluorescence, p-src and src were found in the nucleus, apart from their normal cytoplasmic localization, in androgen-dependent LNCaP cells upon androgen stimulation or deprivation conditions. Also, their localization was not affected by androgen stimulation. Similar to src and p-src, AR as well as pSer81-AR (an AR site indirectly phosphorylated by src) were found in the nucleus as well as in the cytoplasm. Unexpectedly, we found PSA localization in the nucleus upon androgen stimulation in LNCaP and C4-2B cells as well as in the nucleus of C4-2B cells upon androgen deprivation. We further studied the effect of src on AR activity by transfection of dominant negative src (SrcK298M) in LNCaP and androgen-independent C4-2B cells. Transfection with SrcK298M did not affect PSA expression in LNCaP cells whereas in C4-2B cells SrcK298M transfection inhibited PSA expression. These data show that src is required for AR activity and, consequently, PSA expression in androgen-independent prostate cancer cells, but not in androgen-dependent cells. In conclusion, these data suggest that the nuclear co-localization of p-src, AR and PSA might allow macromolecular interactions which can further enhance AR transactivation and promote disease progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-201.
Published Version
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