GSK-3/Rb12 Pathway as a Novel Target of Rapamycin in Prostate Cancer.

摘要

The present study was aimed at determining the role of GSK3/RBL2 pathway in rapamycin-mediated growth arrest in prostate cancer cell. Rapamycin and its derivatives are immunosuppressor drugs that also have a potent tumor suppressor effect. These drugs are currently being evaluated in clinical trials to treat human cancers including prostate cancer. Rapamycin exerts its effects through inhibition of mammalian Target of Rapamycin (mTOR) protein kinase resulting in a decreased expression of a subset of proteins essential for cell cycle progression. The cellular pathway mediating cell cycle arrest by rapamycin is still not fully understood. We proposed that Glycogen Synthase Kinase 3 (GSK3) serves as an important mediator of rapamycin effect. Using small-molecule chemical inhibitors of GSK3 and si-RNA depletion, we demonstrated that GSK3 activity is essential for the induction of G0/G1 arrest by rapamycin in prostate cancer (CaP) cell lines LNCaP and PC3. Chemical inhibition of GSK3 prevented accumulation of RBL2/p130 in rapamycin treated cells. RBL2/p130 is an important regulator of G0/G1 in mammalian cells and the lack of RBL2 /p130 accumulation could account for the reduced effect of rapamycin in the cells treated with GSK3 inhibitors. Importantly, we also found that a prolonged treatment with GSK3 inhibitors results in cytotoxicity in prostate cancer cells. These findings increase our understanding of the mechanism of the tumor-suppressor effect of rapamycin and set the stage for further evaluation of GSK3 as a potential target for anti-cancer therapy.