Sin1 promotes proliferation and invasion of prostate cancer cells by modulating mTORC2-AKT and AR signaling cascades

Aims: Prostate cancer (PCa) is the most common type of cancer and a major cause of death in men worldwide. Aberrant Androgen receptor (AR) and PI3K-AKT signaling are very frequent in PCa patients and, therefore, considered as therapeutic targets in the clinic. Sin1 is an essential component of mTORC2 complex, which determines full AKT activation and PCa development in PTEN-/- mice. Here we examined the role of Sin1 in human PCa cell lines and respective tumor samples. Main methods: Western blotting and immunohistochemistry (IHC) were performed to analyze the expression of Sin1-mTORC2-AKT related proteins in human PCa cells, as well as prostate tumors and normal tissue counterparts. Cell viability and invasion assays were also pursued in the presence or not of Sin1 in PCa cells. Immunoprecipitation assays were additionally carried out to examine the interaction of Sin1 with AR. Key findings: We have presently demonstrated that high levels of Sin1 expression in human PCa tissues correlate with cancer progression. Sin1-mediated cell proliferation and invasion of PCa cells occurs by regulating mTORC2-AKT signaling, epithelial-mesenchymal transition and matrix metalloproteinases. Moreover, androgens are able to induce Sin1 expression, which is further translocated to the nucleus of PCa cells. Finally, Sin1 interacts with AR to suppress its transcriptional activity. Significance: Taken together, these data indicate that both Sin1-mediated mTORC2-AKT signaling and Sin1-AR interaction regulate PCa development. Hence, Sin1 may be considered a novel biomarker of PCa progression.