Abstract 5130: Src and Caveolin-1 reciprocally regulate metastasis via Rho Kinase

Abstract

Abstract In human bladder cancer, overexpression of Caveolin-1 (Cav-1) and downregulation of Src expression and kinase activity correlate with aggressive behavior suggesting they may have causal and perhaps interactive roles in this process. Here we show that Cav-1 and Src are reciprocally expressed in the same tumors, suggesting they act on a similar pathway. RNAi mediated Cav-1 depletion or expression of constitutively active Src in invasive human urothelial cancer cells UMUC-3 and KU-7 resulted in loss of stress fibers and reduced capacity to migrate. Cav-1 depletion was associated with loss of pY14 Cav-1 while increased p190RhoGAP was seen with Src over-expression while both led to a significant reduction in RhoA and RhoC levels and activity. Conversely, expression of Cav-1 but not the non-phosphorylatable mutant of Cav-1 or suppression of Src using PP2 or Src RNAi in noninvasive human urothelial RT4 cancer cells, increased RhoA and RhoC GTP and cell migration. Use of ROCK inhibitor Y27632 in RT4 cells completely abolished enhanced migration induced by Cav-1 expression or that associated with Src inhibition. Furthermore, metastatic lung colonization of UMUC-3 cells expressing constitutively active Src or depleted of Cav-1 was significantly reduced while having marginal effect on subcutaneous tumor growth. Moreover, ROCK inhibitor prevented bladder cancer lung metastasis in vivo. Our findings indicate Src is metastasis suppressor protein in bladder cancer and describe a novel relationship between Cav-1 and Src in regulating RhoA and RhoC providing a unifying molecular mechanism for prior descriptive studies suggesting a role for these proteins in bladder cancer 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 5130.