The metabolism of retinoids and the regulation of gene expression by retinoids via nuclear receptors are profoundly altered in human prostate cancer cells and we hypothesize that these changes contribute to the characteristics of these malignant cells. To define the molecular bases for the failure of many human prostate carcinoma cell lines to express genes involved in retinoid metabolism (e.g. lecithin:retinol acyl transferase), and genes involved in retinoid signaling (e.g. RARs and RXRs), we will study their transcriptional regulation using chromatin immunoprecipitation (ChIP) and real-time RT-PCR assays (AIM 1a). To attempt to restore normal retinoid signaling and growth inhibition pathways in human prostate cancer cells, we will use pharmacological doses of retinoids in combination with other drugs, including RXR (retinoid X receptor) agonists (the omega-3 fatty acid docosahexaenoic acid, phytanic acid), and histone deacetylase inhibitors such as valproic acid (AIM 1b). We will also determine if these drug combinations can restore normal vitamin A (retinol) uptake and metabolism in the human prostate cancer cells (AIM 1c). The functions of enzymes and nuclear receptors in the retinoid signaling pathway will also be tested in two models of prostate cancer: a xenograft model of human tumors and a transgenic model of spontaneous prostate cancer development, the TRAMP model (AIM 2). These animal models will allow us to determine whether retinoid signal transduction abnormalities develop during the process of prostate tumorigenesis, and whether the modulation of retinol uptake and esterification prevents tumors from forming and/or slows tumor progression by altering cell differentiation in the TRAMP model. These experiments will provide insights into the basic mechanisms underlying prostate cancer progression. The knowledge generated from these studies should allow us to devise better pharmacological strategies to reverse specific gene repression and to restore more normal retinoid signaling in malignant cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA097543-01A1
Application #
6867217
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Jhappan, Chamelli
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$265,440
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Larsson, R; Mongan, N P; Johansson, M et al. (2011) Clinical trial update and novel therapeutic approaches for metastatic prostate cancer. Curr Med Chem 18:4440-53
Lee, Mi-Young; Lu, Ailan; Gudas, Lorraine J (2010) Transcriptional regulation of Rex1 (zfp42) in normal prostate epithelial cells and prostate cancer cells. J Cell Physiol 224:17-27
Wang, Rui; Wang, Guoqing; Ricard, Megan J et al. (2010) Smoking-induced upregulation of AKR1B10 expression in the airway epithelium of healthy individuals. Chest 138:1402-10
Scotland, Kymora B; Chen, Siming; Sylvester, Renia et al. (2009) Analysis of Rex1 (zfp42) function in embryonic stem cell differentiation. Dev Dyn 238:1863-77
Touma, Sue Ellen; Perner, Sven; Rubin, Mark A et al. (2009) Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model. Biochem Pharmacol 78:1127-38
Kashyap, Vasundhra; Rezende, Naira C; Scotland, Kymora B et al. (2009) Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev 18:1093-108
Cai, Kun; Gudas, Lorraine J (2009) Retinoic acid receptors and GATA transcription factors activate the transcription of the human lecithin:retinol acyltransferase gene. Int J Biochem Cell Biol 41:546-53
Liu, Limin; Tang, Xiao-Han; Gudas, Lorraine J (2008) Homeostasis of retinol in lecithin: retinol acyltransferase gene knockout mice fed a high retinol diet. Biochem Pharmacol 75:2316-24
Adams, Denise M; Zhou, Tianni; Berg, Stacey L et al. (2008) Phase 1 trial of O6-benzylguanine and BCNU in children with CNS tumors: a Children's Oncology Group study. Pediatr Blood Cancer 50:549-53
Tavares, Trisha S; Nanus, David; Yang, Ximing J et al. (2008) Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther 7:1607-18

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