Abstract 1238: Apigenin suppresses inhibitor of apoptosis family protein expression and disrupts Ku70-bax interaction in prostate cancer cells in culture and in vivo

Abstract

Abstract Apigenin (4′,5,7-trihydroxyflavone), an anticancer agent, selective toxic to cancer cells induces cell cycle arrest and apoptosis. The molecular mechanism(s) of this effect has not been fully elucidated. It is well known that dysfunction of the apoptotic pathway confers apoptosis resistance through inhibitor of apoptosis family protein (IAP) and deregulation of Bax/Bcl2 pathway in prostate cancer cells. In the present study we provide evidence for the mechanisms of apoptosis induction by apigenin. Treatment of androgen-refractory human prostate cancer PC-3 and DU145 cells with 5-40µM apigenin resulted in dose-dependent suppression of XIAP, c-IAP1, c-IAP2 and survivin protein levels. Apigenin treatment (20µM) resulted in significant decrease in cell viability and apoptosis induction with the release of cytochrome C in time-dependent manner. These effects of apigenin were accompanied by decrease in Bcl-xL and Bcl-2 and increase in the active form of Bax protein. The apigenin-mediated increase in Bax was due to dissociation of Bax from Ku70 which is essential for apoptotic activity of Bax. Apigenin treatment resulted in the inhibition of class I histone deacetylases and HDAC1 protein expression, thereby increasing the acetylation of Ku70 and the dissociation of Bax resulting in apoptosis of cancer cells. Furthermore, apigenin significantly reduced HDAC1 occupancy at the XIAP promoter, suggesting that histone deacetylation might be critical for XIAP downregulation. In in vivo studies, per-oral intake of apigenin at doses of 20 and 50µg/mouse/day, two weeks after PC-3 cell implantation, continued for 8 weeks resulted in significant inhibition of tumor volume by 32.5% and 51.3% (P<0.001) and decrease in wet weight tumor by 33.3% and 55.1% (P<0.001), respectively. The animals did not exhibit any signs of toxicity or reduced food consumption. Compared to vehicle-treated controls, induction of apoptosis was significantly increased in tumor xenografts in apigenin fed mice (P<0.001) along with marked reduction in the protein expression of XIAP and survivin in PC-3 tumor xenografts. A dose-dependent decrease in HDAC1 expression, increase in Bax and PARP cleavage was observed in apigenin-treated mice. Taken together, these results suggest that apigenin targets IAP proteins and Ku70-Bax interaction in the induction of apoptosis in prostate cancer cells and in athymic nude mouse xenograft model endorsing its in vivo efficacy. Citation Format: Sanjeev Shukla, Pingfu Fu, Sanjay Gupta. Apigenin suppresses inhibitor of apoptosis family protein expression and disrupts Ku70-bax interaction in prostate cancer cells in culture and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1238. doi:10.1158/1538-7445.AM2014-1238