Abstract
Abstract Characterization of effective chemo-preventive agents for treatment of prostate cancer is an utmost priority. Diosmetin (5, 7-Trihydroxy-4′-methoxyflavone), a natural flavonoid present in citrus plant, has anti-mutagenic and anti-allergic properties. However, the anticancer properties of diosmetin have not been explored in prostate cancer. Present study demonstrates, cell growth inhibition and induction of apoptosis in human prostate carcinoma LNCaP (androgen-responsive) and PC-3 (androgen-refractory) cells by diosmetin, however, no significant growth inhibition observed in normal prostate epithelial cells (RWPE1). Cell growth is a fundamental biological process, where mTOR (mammalian target of rapamycin) pathway has its role, regulates cell growth by coordinating energy and nutrient signals with growth factor. mTOR protein kinase have two different complexes; complex-I contains major component raptor; a target of rapamycin and complex II; insensitive to rapamycin, has major component rictor. Rictor is important as it phosphorylates Ser-473 of Akt/PKB, which is essential for full Akt/PKB activation. We observed diosmetin treated prostate cancer cells was able to inhibit growth factor (IGF-1) and cytokine (IL-6) induced rictor expression. Furthermore, diosmetin (20μM) treatment to prostate cancer cells prevented rictor nuclear localization and subsequently inhibited phospho-Akt (Ser-473), which subsequently resulted in increased FOXO3a nuclear presence. Downstream pathway p70S6 kinase, which has a critical role in cell cycle, growth and survival, was also inhibited after diosmetin treatment. These effects were associated with a marked decrease in the protein expression of cyclin D1 and their activating partner, cyclin-dependent kinase (cdk) 2 and 4 with concomitant upregulation of KIP1/p27 and INK4a/p16. Additionally diosmetin treatment to these cells modulated cell survival machinery by down regulating key molecules viz., c-Myc, Survivin and XIAP (X-Linked Inhibitor of Apoptosis). Diosmetin treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with an increase in cleaved caspase-3. Taken together, our studies demonstrate that diosmetin-mediated growth inhibition and induction of apoptosis in both LNCaP and PC-3 cells were due to deregulated levels of rictor and Akt signaling cascade and modulation of cell-cycle machinery. We are documenting these evidences for the first time that diosmetin acts against potential molecular targets to alter cellular events to elicit anticancer effects in prostate cancer cells. Citation Format: Rebecca Pakradooni, Riddhi Patel, Janmejai K. Srivastava, Sanjeev Shukla. In-vitro growth inhibitory effects of diosmetin on human 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 4626.
Published Version
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