Abstract 253: Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer

Overexpression of chromatin modifier protein, metastasis-associated protein 1 (MTA1) in prostate cancer contributes to tumor aggressiveness and metastasis. MTA1 ChiP-Seq analysis identified downstream targets that are transcriptionally regulated by MTA1 and suggested a link between MTA1 and ETS2. The effects of ETS2 in cancer are context-dependent and both oncogenic and tumor suppressive functions have been described. We have shown that there is a positive correlation between MTA1 and ETS2 using loss of function studies and various preclinical models of prostate cancer. Our conclusion that MTA1 functions as a co-activator for regulating ETS2 expression in prostate cancer leading to promotion of prostate cancer progression, prompted us to look for pharmacological inhibitors of MTA1/ETS2 axis. In our previous studies, we reported inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of PIN and adenocarcinoma in xenografts and transgenic mouse models by inhibiting MTA1 expression and signaling. Here, we found that Gnetin C, double-resveratrol, has more potent inhibition of MTA1/ETS2 axis than other stilbenes. Gnetin C, a resveratrol dimer, is found abundantly in melinjo plant widely cultivated in Southeast Asia; its seeds and fruits are common ingredients in Indonesian culinary. As resveratrol and pterostilbene, Gnetin C has been reported to possess anti-inflammatory and anticancer activity, however it has not been considered as chemopreventive agent in prostate cancer. Using two prostate cancer cell lines, namely DU145 and PC3M cells, we found that Gnetin C shows significant inhibitory effect on cell proliferation, more potent effects in colony formation and wound healing assays than resveratrol or pterostilbene. Importantly, Gnetin C specifically and strongly downregulates MTA1 and ETS2 expression in prostate cancer cells. Taken together, our findings implicate the potential of Gnetin C in MTA1/ETS2-mediated chemoprevention and therapy in prostate cancer. Citation Format: Urvi Kolhatkar, Kshiti Dholakia, Gabriela Sikorska, Avinash Kumar, Luis A. Martinez, Anait S. Levenson. Gnetin C as a candidate for targeted chemopreventive and therapeutic measures in prostate cancer [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 253.