Abstract 3507: Rhamnetin enhances anti-proliferative and apoptotic effects on prostate cancer cells

Abstract

Abstract Dysregulation of oxidative stress plays important role in both tumor development and response to anticancer drug treatment. Increased oxidative stress induces reactive oxygen species (ROS) which stimulate genes viz. FoxO3a and Klotho. Klotho modulates stress-induced senescence, whereas forkhead transcription factor; FoxO3a is known to involve in antioxidant, anti-proliferative and tumor suppressor functions. We have previously demonstrated that FoxO3a is deregulated in human prostate adenocarcinoma and in transgenic adenocarcinoma of the mouse prostate (TRAMP) model that mimics progressive forms of human disease. Here we demonstrate the potential involvement of Klotho protein in prostate cancer progression and using a natural agent; rhamnetin as anticancer in TRAMP mice modulated Klotho and FoxO3a signaling by altering ROS to inhibit prostate cancer. Per-oral feeding of rhamnetin at 10- and 20-μg/mouse/day (gavaged in 0.2 ml vehicle containing 0.5% methyl cellulose and 0.025% Tween 20) to TRAMP mice for six days per week for 16 weeks, starting at 8 weeks of age, exhibited marked reduction in tumor growth. Rhamnetin intake led to increased antioxidant potentials, which was evident from increased levels of klotho, Nrf2 and with significantly increased expression of Shc66 in the dorso-lateral prostate. Reports suggested that secretory klotho binds to multiple FGFRs (fibroblast growth factor receptors) with different affinity. However, TRAMP mice exhibited significantly increased FGFR1 expression in dorso-lateral prostates, which were reduced significantly after rhamnetin feeding to TRAMP mice. Furthermore, inhibited FGFR1 expression resulted in reduced phospho-Akt (Ser-473) and ERK1/2 phosphorylation in rhamnetin fed mice than control. This modulated signaling cascade decreased nuclear presence of p-Akt (Ser-473), which restricted FoxO3a phosphorylation and led to nuclear retention in dorso-lateral prostate. Increased nuclear presence of FoxO3a elevated transcriptional activity and expression of FoxO-dependent apoptotic protein, Bim. Moreover, rhamnetin feeding to TRAMP mice reduced Alix expression, which further helped in accelerating apoptotic machinery. Similarly rhamnetin treatment to human prostate cancer LNCaP and PC-3 cells also resulted in the restoration of Klotho and FoxO3a in the nucleus. Increase nuclear presence of Klotho and FoxO3a protein may be a decisive factor for increase resistance to oxidative stress and inhibited prostate cancer progression. Our finding suggests that rhamnetin may be developed as a preventive agent in prostate cancer. Citation Format: Riddhi Patel, Rebecca Pakradooni, Christine Oak, Natarajan Bhaskaran, Sanjeev Shukla. Rhamnetin enhances anti-proliferative and apoptotic effects on prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3507.