The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer

Abstract

The molecular mechanisms leading to prostate cancer remain poorly understood, especially concerning the progression to the metastatic form. SSeCKS, a major protein kinase C substrate with tumor suppressor activity, is likely the rodent orthologue of human Gravin/AKAP12, a scaffolding protein for protein kinases A and C. Gravin was mapped as a single-copy gene to 6q24-25.2, a hotspot for deletion in advanced prostate cancer, and therefore, we investigated the role of SSeCKS/Gravin in prostate oncogenesis. SSeCKS/Gravin protein was detected in untransformed rat and human prostate epithelial cell lines EP12 and PZ-HPV-7, respectively, and in human prostatic epithelium, especially basal epithelial cells. In contrast, SSeCKS/Gravin protein and RNA levels were severely reduced in human (PC-3, PPC-1, LNCaP, DU145, and TSU) and rat Dunning (AT3.1 and MatLyLu) prostate cancer cell lines. The regulated reexpression of SSeCKS in MatLyLu cells induced filopodia-like projections and a decrease in anchorage-independent growth. In nude mice, SSeCKS reexpression slightly decreased primary-site tumor growth but severely decreased the formation of lung metastases. Primary-site tumors that progressed lost regulated SSeCKS reexpression. SSeCKS/Gravin expression was detected in benign human prostatic lesions and well-differentiated carcinomas but not in undifferentiated lesions with Gleason sums > or =6. Our data suggest a role for the loss of SSeCKS/Gravin in the metastatic progression of human prostate cancer.