The proposed study will determine the chemo-preventive potential of diosmetin, a natural plant flavanol, in regulating Rictor; the core constituent and critical protein in the function of mTORC2 (rapamycin- insensitive) protein complex to prevent prostate cancer progression. The role of Rictor has been reported in colon, breast and ovarian cancers. Circulating growth factors phosphorylates Rictor protein at Thr-1135 in prostate cancer cells, moreover, increased presence of rictor results in series of events including phosphorylation of PKCa and Akt molecules. Both these molecules play significant role in cell survival, cell adhesion, cell transformation and cell cycle regulation. It has been demonstrated that rapamycin, the known inhibitor of mTOR kinase pathway has no inhibitory effect on Rictor (mTORC2 main component). The urgent need is to identify an effective agent that can regulate Rictor and its associated events PKCa and Akt to prevent prostate cancer progression. Diosmetin has anti- inflammatory, anti-oxidants and anticancer effects. The proposed study will explore the preventive role of diosmetin in targeting Rictor, its phosphorylation and also its associated signaling events in prostate cancer. The in vitro and in vivo studies will determine whether diosmetin has potential to inhibit Rictor, its phosphorylation, and additionally maintain rictor's presence to regulate kinase activities of PKCa and Akt at appropriate level, thereby resulting in reduced prostate cancer cell proliferation and tumor progression. Our long term goal is to develop diosmetin as safe and an effective chemopreventive agent for prostate cancer and to understand the role of Rictor in prostate cancer progression. Public Health Significance: There is an immediate need for an effective and clinically relevant strategy to inhibit prostate cancer, with minimal side-effects. Hereby using a natural agent from citrus fruits and herbal preparations, the potential of diosmetin will be tested against prostate cancer. Since prostate cancer is the second largest killer in the United States males, reducing deaths from this deadly form of disease is urgently needed.

Public Health Relevance

This proposal will determine the potentials of diosmetin; a natural agent, against prostate cancer in in vitro and in in vivo model systems (spontaneous mouse model as well as in mouse orthotopic prostate cancer model) by targeting Rictor in regulating its associated dysregulated kinases Akt and PKCa. Results obtained from the proposed studies will provide critical supportive data and strong evidence to further test diosmetin as a means to prevent prostate cancer progression in high risk subjects.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1)
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Emenaker, Nancy J
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Case Western Reserve University
Schools of Medicine
United States
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Oak, Christine; Khalifa, Ahmad O; Isali, Ilaha et al. (2018) Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. Int J Oncol 53:835-843
Patel, Riddhi; Khalifa, Ahmad O; Isali, Ilaha et al. (2018) Prostate cancer susceptibility and growth linked to Y chromosome genes. Front Biosci (Elite Ed) 10:423-436