In our endeavor to identify new, less-toxic therapies for prevention and treatment of human prostate cancer, we propose to study a dietary agent resveratrol, a polyphenolic compound found in grapes and wine. Resveratrol exerts striking inhibitory effects on diverse cellular events associated with tumor initiation, promotion and progression, thus holds great promise for development as a chemopreventive agent for prostate cancer. Furthermore, resveratrol sensitizes prostate cancer cells to TRAIL (TNF-related apoptosis-inducing ligand), which is a biologically important cytokine. Besides these advances, the intracellular mechanisms by which resveratrol inhibits proliferation and induces apoptosis in tumor cells are not fully defined. Overall rationale for the evaluation of efficacy of resveratrol against prostate cancer comes from epidemiological data and from our preliminary studies. We hypothesize that resveratrol will be highly effective in suppressing growth of human prostate cancer cells, due to its ability to (a) induce apoptosis through upregulation of death receptors and proapoptotic members of the Bcl-2 family and activation of caspases, and (b) activate FOXO family of transcription factors.
The specific aims of the project are: (1) To determine the intracellular mechanisms by which resveratrol inhibits proliferation and induces apoptosis in human prostate cancer cells; and to determine the molecular mechanisms by which resveratrol sensitizes prostate cancer cells to TRAIL; (2) To examine the mechanisms by which FOXO family of transcription factors regulate the Bcl-2 family members, cell cycle regulatory genes and apoptosis in prostate cancer cells treated with resveratrol; and (3) To determine the effect of resveratrol and TRAIL on growth of human prostate cancer xenografts in vivo in nude mice, and to determine the mechanism of resveratrol and TRAIL-mediated in vivo growth inhibition of prostate cancer xenografts. Specifically, studies are designed to determine the contribution of mitochondrial and/or death receptor pathways, and PI3-K/Akt/FOXO activity in resveratrol-induced apoptosis. The down-stream apoptosis-related targets of FOXO transcription factors will be identified. The interactive effects of the resveratrol and TRAIL will be assessed in terms of xenograft growth and tumor regression. Thus, resveratrol based strategies can be utilized for prevention and treatment of prostate cancer, and in the long-term it may have profound impact on the overall incidence of human prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114469-03
Application #
7036480
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Kim, Young Shin
Project Start
2005-07-01
Project End
2009-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$170,752
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772337
City
Tyler
State
TX
Country
United States
Zip Code
75708
Marsh, Justine L; Jackman, Chris P; Tang, Su-Ni et al. (2014) Embelin suppresses pancreatic cancer growth by modulating tumor immune microenvironment. Front Biosci (Landmark Ed) 19:113-25
Huang, Minzhao; Tang, Su-Ni; Upadhyay, Ghanshyam et al. (2014) Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and Sonic hedgehog pathways. PLoS One 9:e92161
Huang, Minzhao; Tang, Su-Ni; Upadhyay, Ghanshyam et al. (2014) Rottlerin suppresses growth of human pancreatic tumors in nude mice, and pancreatic cancer cells isolated from Kras(G12D) mice. Cancer Lett 353:32-40
Fu, Junsheng; Rodova, Mariana; Roy, Sanjit K et al. (2013) GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Cancer Lett 330:22-32
Shankar, Sharmila; Kumar, Dhruv; Srivastava, Rakesh K (2013) Epigenetic modifications by dietary phytochemicals: implications for personalized nutrition. Pharmacol Ther 138:1-17
Shankar, Sharmila; Marsh, Luke; Srivastava, Rakesh K (2013) EGCG inhibits growth of human pancreatic tumors orthotopically implanted in Balb C nude mice through modulation of FKHRL1/FOXO3a and neuropilin. Mol Cell Biochem 372:83-94
Zhao, Min; Tang, Su-Ni; Marsh, Justin L et al. (2013) Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice. Cancer Lett 337:210-7
Fu, Junsheng; Rodova, Mariana; Nanta, Rajesh et al. (2013) NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200. Neuro Oncol 15:691-706
Tang, Su-Ni; Fu, Junsheng; Nall, Dara et al. (2012) Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int J Cancer 131:30-40
Tang, Su-Ni; Fu, Junsheng; Shankar, Sharmila et al. (2012) EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS One 7:e31067

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