Abstract 2895: Verteporfin targets p62 in prostate cancer therapeutics

To test the hypothesis that p62 is an optimal target for autophagy inhibition and Verteporfin, a clinically available drug approved by FDA to treat macular degeneration that inhibits autophagy by targeting p62 protein, can be developed clinically to improve therapy for advanced prostate cancer. Results showed that Verteporfin inhibited cell growth and colony formation in PC-3 cells. Verteporfin generated crosslinked p62 oligomers, resulting in inhibition of autophagy and constitutive activation of Nrf2 as well as its target proteins, Bcl-2 and TNF-α. In normal prostate epithelial cells, forced expression of p62 caused constitutive Nrf2 activation and development of apoptosis resistance and Verteporfin treatment exhibited inhibitory effects. Verteporfin treatments also inhibited starvation-induced autophagic influx of these cells. Verteporfin inhibited tumorigenesis of both normal prostate epithelial cells with p62 expression and prostate cancer cells and decreased p62, constitutive Nrf2, and Bcl-xL in xenograft tumor tissues, indicating that p62 can be developed as a drug target against prostate cancer. So p62 has a high potential to be developed as a therapeutic target. Verteporfin represents a prototypical agent with therapeutic potential against prostate cancer through inhibition of autophagy by a novel mechanism of p62 inhibition. Citation Format: Lei Wang, Donghern Kim, James Wise, Xianglin Shi, Zhuo Zhang, Robert S. DiPaola. Verteporfin targets p62 in prostate cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2895.