Abstract 252: Prostate carcinogenesis inhibition through AKT-PKCα signaling pathway by diosmetin

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Abstract Mammalian target of rapamycin (mTOR) integrates nutrient and mitogen signals to regulate cell growth (increased cell mass and cell size) and cell division. mTOR protein kinase have two different complexes; complex-I contains major component raptor, whereas complex II (insensitive to rapamycin), has major component rictor. Rictor plays a critical role in AKT (Ser-473 phosphorylation), which facilitates phosphorylation of AKT on Thr-308 by PDK1 for full activation. When we genetically disrupted Rictor, it decreased AKT phosphorylation (Ser-473) and impaired PKCα (Ser-657) expressions. Growth factors viz., IGF-1 and IL-6 are the major player in prostate cancers, these increases Rictor expression. We need to have an agent that can modulate kinase activity of AKT and PKCα to inhibit prostate cancer cell growth. Diosmetin (5, 7-Trihydroxy-4′-methoxyflavone) could be such an agent. Diosmetin, a natural flavone present in plant legumes, has anti-mutagenic and anti-allergic properties. Diosmetin inhibited IGF-1 and IL-6 induced rictor expression in LNCaP and PC-3 prostate cancer cells. Diosmetin dose response treatment to these cells inhibited cell growth and induced apoptosis with no significant growth inhibition in normal prostate epithelial cells (RWPE1). Diosmetin treatment to prostate cancer cells modulated cell survival machinery by down regulating key molecules viz., c-Myc, Survivin and XIAP (X-Linked Inhibitor of Apoptosis). Similarly diosmetin (20 and 50μg/animal/day) feeding to nude mice models, which were orthotopically implanted with luciferase tag PC-3 cells in ventral prostate represented significant decrease in tumor volume than control mice. Diosmetin fed tumor bearing mice reduced phosphorylation of Rictor, (Thr-1135), AKT (Ser-473) and PKCα (Ser-657) expressions to inhibit tumor growth significantly. Moreover, luciferase activity of implanted tumor decreased after diosmetin dose response feeding than control mice. Additionally bone radiographic images suggested that diosmetin treatment inhibited homing of PC-3 cells in the bone. These effects were associated with decrease in cyclin D1 expression and their activating partner, cyclin-dependent kinase (cdk) 2 and 4 with concomitant upregulation of p27/KIP1. Further diosmetin treatment induced apoptosis which was evident by increased expression of cleaved caspase-3. We are documenting these evidences for the first time in animal model system that diosmetin acts against potential molecular targets to alter cellular events to elicit anticancer effects in prostate cancer. Citation Format: Rebecca Pakradooni, Ahmad Khalifa, Ilaha Isali, Sanjeev Shukla. Prostate carcinogenesis inhibition through AKT-PKCα signaling pathway by diosmetin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 252.