Abstract 2653: Nelfinavir induces apoptosis in hormone-resistant prostate cancer cells through inhibition of regulated intramembrane proteolysis of SREBP-1 and ATF6

Abstract

Abstract We previously reported that nelfinavir-induced apoptosis in liposarcoma is a direct result of regulated intramembrane proteolysis (RIP) inhibition mediated through inhibition of site-2 protease (S2P) activity. We now report similar effects in hormone-resistant prostate cancer (HR-PC) cells. Nelfinavir-mediated RIP inhibition leads to accumulation of unprocessed sterol regulatory element binding protein-1 (SREBP-1) and activating transcription factor 6 (ATF6). This results in endoplasmic reticulum (ER) stress and inhibition of the unfolded protein response (UPR), which leads to autophagy and caspase activation. Confocal microscopy and proliferation studies demonstrate that nelfinavir inhibits the nuclear translocation of SREBP-1-EGFP and ATF6-EGFP fusion proteins, and reduces PC proliferation, similar to the situation observed in site-1 protease (S1P) and S2P-siRNA knockdown cells. Western blotting in nelfinavir and S1P and/or S2P-siRNA knockdown cells confirms accumulation of precursor SREBP-1 and ATF6. Treatment of PC cells with DCI, an S1P inhibitor did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P inhibitor, reproduces the molecular and biological phenotype observed in nelfinavir-treated HR-PC cells. These results are consistent with the hypothesis that S2P is a target of nelfinavir. These findings, together with our previous report, provide new insight into the mechanism of nelfinavir-mediated induction of ER stress and cell death in cancer, and are the first to report targeting S2P therapeutically for cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2653. doi:10.1158/1538-7445.AM2011-2653