Abstract 5865: Gartanin, a 4-prenylated xanthone in the mangosteen fruit, inhibits the growth of prostate cancer cells associated with Skp2 degradation via neddylation inhibition and FBXW2 induction

Abstract

Abstract The S-phase kinase-associated protein 2 (Skp2) is overexpressed in prostate cancer and associated with tumor stage, disease recurrence, and worse patient survival. Studies also have demonstrated that Skp2 overexpression plays a critical role in development and progression of prostate cancer in several prostate cancer models, including PTEN knockout and TRAMP carcinogenesis and CWR22 xenograft models. Therefore, Skp2 is a promising target for developing new therapeutic and preventive approaches for prostate cancer. Here, we have found that gartanin, 4-prenylated xanthone from the Garcinia mangostana fruit (mangosteen), promoted Skp2 degradation in a proteasome-dependent manner in prostate cancer cells. In addition, gartanin induced the expression of FBXW2, a novel E3 ligase of SKP2 for targeted degradation, and downregulated the expression of NEDD8, leading to reduced neddylation levels of UBC12 and Cullin1. Molecular modelling analysis predicts that gartanin reasonably docks onto the regulatory subunit of NEDD8 activating enzyme E1 (NAE1) and next to the NEDD8 binding complex. More interestingly, gartanin selectively inhibits the growth of Skp2 overexpressing PC3 cells compared to parental PC cells (IC50 values for PC3/Skp2 vs. PC3 cells are approximately 4 μM vs. 14 μM). Together, our data indicate that gartanin is a novel natural agent for targeting Skp2 degradation via induction of FBXW2 expression and inhibition of neddylation. Gartanin deserves further investigation for its usefulness in prostate cancer prevention and treatment. Citation Format: Victor Pham, Michelle Bui, Raymond Rendon, Ericka Agredano, Thanh Le, Liankun Song, Xiaolin Zi. Gartanin, a 4-prenylated xanthone in the mangosteen fruit, inhibits the growth of prostate cancer cells associated with Skp2 degradation via neddylation inhibition and FBXW2 induction [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 5865.