Abstract 1913: Rhamnetin inhibits prostate cancer progression in an autochthonous mouse prostate cancer model

Abstract

Abstract Aging increases oxidative stress and cancer risk. Age-regulated genes viz. FoxO3a and Klotho are stimulated by reactive oxygen species (ROS) due to increased oxidative stress. Klotho, an antiaging gene, modulates stress-induced senescence, and decreases with advancing age, whereas forkhead transcription factor, FoxO3a is known to involve in a paradigm that engages 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 anticancer effects of rhamnetin, a dietary flavonoid present in fruits and vegetables, in modulating Klotho and FoxO3a signaling by suppressing ROS. 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 with no signs of metastasis. Rhamnetin feeding to TRAMP resulted in a significant dose-dependent reduction in FoxO3a, in the dorso-lateral prostates. FoxO3a protein was redistributed more in nuclear than the cytosolic compartments after rhamnetin feeding. Simultaneously, decreased FoxO3a phosphorylation (Ser-253) was observed in the dorso-lateral prostate, which correlated with decreased cytoplasmic retention of FoxO3a with no significant changes in 14-3-3 chaperone protein in the cytosol after rhamnetin feeding. Additionally, decreased IGF-1 protein expression with subsequent decrease in p-Akt (Ser-473) and p-Erk1/2 (Thr202/Tyr204) was observed after rhamnetin feeding demonstrating that the decreased nuclear presence of p-Akt (Ser-473) may restrict FoxO3a phosphorylation and its retention in the nucleus along with decreased p-Erk1/2 levels in the dorso-lateral prostate. Furthermore, rhamnetin intake led to increased levels of SOD2 and significantly enhanced the expression of the thioredoxin/peroxiredoxin (Trx/Prx) in the dorso-lateral prostate. Similar findings were recorded in cell culture studies where rhamnetin treatment to human prostate cancer LNCaP and PC-3 cells resulted in the restoration of Klotho and FoxO3a in the nucleus. This increase in Klotho and FoxO3a protein expressions in the nucleus may be a decisive factor for increase resistance to oxidative stress and cancer progression. Our finding suggests that rhamnetin has potential to modulate Klotho and FoxO signaling cascades and could be represented as therapeutic targets in prostate cancer. Citation Format: Christine Oak, Natarajan Bhaskaran, Sanjay Gupta, Sanjeev Shukla. Rhamnetin inhibits prostate cancer progression in an autochthonous mouse prostate cancer model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1913. doi:10.1158/1538-7445.AM2015-1913