Our research focuses on natural compounds that possess chemotherapeutic and/or chemopreventive properties with respect to cancer. In the proposed study, we will characterize the mechanism of action of the compound Withaferin-A (WA), a bioactive compound of Withania somnifera, which is extensively used in Asian and African traditional medicine. WA displays impressive and selective activity against androgen- dependent and androgen-independent prostate cancer (ADPC and AIPC, respectively), of which the latter is refractory to all current forms of treatment. Our preliminary in vitro and in vivo data indicate WA targets ADPC and AIPC cells by inhibiting the activity of Akt, a protein kinase that activates cell survival pathways. Our preliminary data demonstrate that, concomitant to Akt inhibition in ADPC and AIPC cells, WA activates FOXO3a, which in turn activates prostate apoptosis response-4 (Par-4), a protein that selectively induces apoptosis in cancer cells Based on our results, we hypothesize WA overrides the negative effects of Akt on CREB/Par-4 signaling to achieve chemopreventive and/or chemotherapeutic effects on AIPC. To address this hypothesis, we propose the following aims: investigate the interaction between Akt/CREB and Par-4 signaling, (Aim 1);and how WA modulates the pro-apoptotic signaling in AIPC (Aim 2);evaluate the effects of WA on androgen- -independent prostate tumor growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) model (Aim 3);and examine the mechanisms of WA-mediated tumor inhibition in TRAMP and/or TRAMP cell lines (Aim 4). For the in vitro arm of our studies we will use a variety of approaches (immunoprecipitation, siRNA strategies, immunofluorescence, Western blot, Northern blots, Chip assays, siRNA strategies, pull down assays, pharmacological blocking) in order to determine the molecular junction at which Akt/CREB 3aand Par-4 converge. For our in vivo studies, we will conduct tumor regression studies, yet we will also examine histopathology, cell death, expression patterns of pro-survival proteins and pro-apoptotic proteins in the tumor tissues, and WA levels in the serum and prostate tissue. Our long term goal is to promote natural compounds to a clinical environment, where these agents can be thoroughly assessed for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is a potential candidate for such clinical evaluation, and our proposed studies will elucidate at a mechanistic level its potency against prostate cancer, both from a chemopreventive and chemotherapeutic standpoint.

Public Health Relevance

Prostate cancer (PCa) remains a major cause of cancer-related death, and at advanced stages current therapy is ineffective. Intervention with dietary compounds for the prevention and/or treatment of prostate cancer is a relatively new area of research focused on signal transduction pathways, which has resulted in the development of important new therapeutics for specific malignancies. The proposed study of dietary supplement Withaferin-A (WA), the major bioactive compound from Withania somnifera), is designed to provide essential insights at the molecular level into the mechanism of action of Withaferin-A against prostate cancer and may ultimately lead to clinical evaluation of its potential for chemoprevention and/ or chemotherapy in prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-OTC-B (02))
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Malone, Winfred F
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University of Louisville
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Dahiya, Nisha R; Chandrasekaran, Balaji; Kolluru, Venkatesh et al. (2018) A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer. Mol Carcinog 57:1332-1341
Moselhy, Jim; Suman, Suman; Alghamdi, Mohammed et al. (2017) Withaferin A Inhibits Prostate Carcinogenesis in a PTEN-deficient Mouse Model of Prostate Cancer. Neoplasia 19:451-459
Suman, Suman; Das, Trinath P; Moselhy, Jim et al. (2016) Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model. Oncotarget 7:53751-53761
Damodaran, Chendil; Das, Trinath P; Papu John, A M Sashi et al. (2016) miR-301a expression: A prognostic marker for prostate cancer. Urol Oncol 34:336.e13-20
John, Am Sashi Papu; Ankem, Murali K; Damodaran, Chendil (2016) Oxidative Stress: A Promising Target for Chemoprevention. Curr Pharmacol Rep 2:73-81
Das, T P; Suman, S; Alatassi, H et al. (2016) Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer. Cell Death Dis 7:e2111
Das, Trinath P; Suman, Suman; Papu John, A M Sashi et al. (2016) Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer. Cancer Lett 377:134-9
Moselhy, Jim; Srinivasan, Sowmyalakshmi; Ankem, Murali K et al. (2015) Natural Products That Target Cancer Stem Cells. Anticancer Res 35:5773-88
Luevano, Joe; Damodaran, Chendil (2014) A review of molecular events of cadmium-induced carcinogenesis. J Environ Pathol Toxicol Oncol 33:183-94
Roy, Ram V; Suman, Suman; Das, Trinath P et al. (2013) Withaferin A, a steroidal lactone from Withania somnifera, induces mitotic catastrophe and growth arrest in prostate cancer cells. J Nat Prod 76:1909-15

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