Abstract 617: Apigenin intake regulates Fox ‘O’ signaling in an autochthonous mouse model of prostate cancer

Abstract

Abstract Forkhead transcription factors of ‘O’ class (FoxOs) are involved in a paradigm that supports proliferation, survival, longevity during multiple cellular environments, and tumor development. Perturbation of FOXO activity leads to altered cellular response which results in cancer development and progression. We previously showed that FOXO signaling is deregulated in human prostate adenocarcinoma and in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model that mimics progressive forms of human disease. In the present study we aimed to demonstrate the potential role of apigenin, a common dietary flavonoid present in fruits and vegetables, in modulating FoxO signaling and its downstream events to suppress cancer progression using in vivo and in vitro models. Apigenin was fed to TRAMP mice at 20- and 50- μg/mouse/day (gavaged in 0.2 ml vehicle containing 0.5% methyl cellulose and 0.025% Tween 20) for six days in a week for 20 weeks; whereas control animals received vehicle only. Apigenin intake by TRAMP mice from 8-28 weeks of age exhibited marked reduction in tumor growth with no signs of metastasis. Apigenin feeding to TRAMP resulted in a significant dose-dependent reduction in Foxo3a, but not Foxo1a protein observed in the dorso-lateral prostates. Foxo3a protein was redistributed more in nuclear than the cytosolic compartments after apigenin feeding. Simultaneously, decreased Foxo3a phosphorylation (Ser253) was observed in the dorso-lateral prostate, which correlated with decreased cytoplasmic retention of Foxo3a with no significant change in 14-3-3 chaperone protein in the cytosol after apigenin feeding. Conversely, TRAMP mice have higher 14-3-3 expression than non-transgenic mice and this higher level accounted for nuclear retention of Foxo3a. A subsequent decrease in p-Akt (Ser473) was noted after apigenin feeding demonstrating that the decreased nuclear presence of p-Akt (ser473) may be restricting Foxo3a phosphorylation and its retention in the nucleus. Furthermore, an increase in the levels of MnSOD and Cu/ZnSOD was observed in TRAMP mice after apigenin intake. Similar findings were recorded in cell culture studies where apigenin treatment to human prostate cancer LNCaP and PC-3 cells resulted in the restoration of FOXO3a in the nucleus. This increase in Foxo3a protein levels in the nucleus may be a decisive factor resulting in the inhibition of prostate cancer. These finding suggests that apigenin has potential role in regulating the FOXO signaling cascade and may be a major therapeutic target in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 617. doi:1538-7445.AM2012-617