Metabolism of Vitamin A in the Prostate

Summary

Principal Investigator: Lorraine Gudas
Abstract: 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.
Funding Period: 2005-03-01 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. ncbi Clinical trial update and novel therapeutic approaches for metastatic prostate cancer
    R Larsson
    Division of Organic Chemistry, Lund University, 221 00, Lund, Sweden
    Curr Med Chem 18:4440-53. 2011
  2. pmc Smoking-induced upregulation of AKR1B10 expression in the airway epithelium of healthy individuals
    Rui Wang
    Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA
    Chest 138:1402-10. 2010
  3. pmc Transcriptional regulation of Rex1 (zfp42) in normal prostate epithelial cells and prostate cancer cells
    Mi Young Lee
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
    J Cell Physiol 224:17-27. 2010
  4. pmc Analysis of Rex1 (zfp42) function in embryonic stem cell differentiation
    Kymora B Scotland
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10065, USA
    Dev Dyn 238:1863-77. 2009
  5. pmc Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model
    Sue Ellen Touma
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Biochem Pharmacol 78:1127-38. 2009
  6. pmc 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
    Vasundhra Kashyap
    Department of Pharmacology, Graduate Programs in Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    Stem Cells Dev 18:1093-108. 2009
  7. pmc Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment
    Trisha S Tavares
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
    Cancer Biol Ther 7:1607-18. 2008
  8. pmc Retinoic acid receptors and GATA transcription factors activate the transcription of the human lecithin:retinol acyltransferase gene
    Kun Cai
    Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA
    Int J Biochem Cell Biol 41:546-53. 2009
  9. pmc Homeostasis of retinol in lecithin: retinol acyltransferase gene knockout mice fed a high retinol diet
    Limin Liu
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
    Biochem Pharmacol 75:2316-24. 2008
  10. ncbi Phase 1 trial of O6-benzylguanine and BCNU in children with CNS tumors: a Children's Oncology Group study
    Denise M Adams
    Cincinnati Children s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
    Pediatr Blood Cancer 50:549-53. 2008

Scientific Experts

  • Denise M Adams
  • Lorraine J Gudas
  • Xiao Han Tang
  • Limin Liu
  • Kymora B Scotland
  • Moo Jin Suh
  • R Larsson
  • Mi Young Lee
  • Rui Wang
  • Sue Ellen Touma
  • Kun Cai
  • Vasundhra Kashyap
  • Trisha S Tavares
  • Nigel P Mongan
  • Marni Sheren-Manoff
  • Jay D Raman
  • J L Persson
  • L Shcherbina
  • P A Abrahamsson
  • N P Mongan
  • M Johansson
  • O Sterner
  • L J Gudas
  • Guoqing Wang
  • Ailan Lu
  • Yael Strulovici-Barel
  • Neil R Hackett
  • Jacqueline Salit
  • Ronald G Crystal
  • Megan J Ricard
  • Barbara Ferris
  • Siming Chen
  • Jenny Liao Persson
  • David M Nanus
  • Naira C Rezende
  • Renia Sylvester
  • Sebastian M Shaffer
  • Sven Perner
  • Mark A Rubin
  • David Nanus
  • Ximing J Yang
  • Rong Li
  • Dan Su
  • Dean Bok
  • Sandra J Shin
  • Robert R Rando
  • Satish K Tickoo
  • Douglas S Scherr
  • Stephen A Boorjian

Detail Information

Publications15

  1. ncbi Clinical trial update and novel therapeutic approaches for metastatic prostate cancer
    R Larsson
    Division of Organic Chemistry, Lund University, 221 00, Lund, Sweden
    Curr Med Chem 18:4440-53. 2011
    ..We also discuss potential molecular targets for new drug candidates for the treatment of metastatic PCa...
  2. pmc Smoking-induced upregulation of AKR1B10 expression in the airway epithelium of healthy individuals
    Rui Wang
    Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA
    Chest 138:1402-10. 2010
    ..We hypothesized that upregulation of AKR1B10 expression may be initiated in healthy smokers prior to the development of evidence of lung cancer...
  3. pmc Transcriptional regulation of Rex1 (zfp42) in normal prostate epithelial cells and prostate cancer cells
    Mi Young Lee
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
    J Cell Physiol 224:17-27. 2010
    ..This lack of positive transcriptional regulation by the hRex1 protein may be responsible for the lack of Rex1 expression in PC-3 prostate cancer cells...
  4. pmc Analysis of Rex1 (zfp42) function in embryonic stem cell differentiation
    Kymora B Scotland
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10065, USA
    Dev Dyn 238:1863-77. 2009
    ..These data, taken together, suggest that Rex1 influences differentiation, cell cycle regulation, and cancer progression...
  5. pmc Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model
    Sue Ellen Touma
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Biochem Pharmacol 78:1127-38. 2009
    ..Our data indicate that this reduction in ALDH1A2 protein is an early event in human prostate cancer...
  6. pmc 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
    Vasundhra Kashyap
    Department of Pharmacology, Graduate Programs in Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    Stem Cells Dev 18:1093-108. 2009
    ....
  7. pmc Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment
    Trisha S Tavares
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
    Cancer Biol Ther 7:1607-18. 2008
    ..Together, our results show that treatment of RCC with cRA and/or SAHA increases the expression of several genes and gene families that result in reduced cell proliferation...
  8. pmc Retinoic acid receptors and GATA transcription factors activate the transcription of the human lecithin:retinol acyltransferase gene
    Kun Cai
    Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA
    Int J Biochem Cell Biol 41:546-53. 2009
    ..In summary, our data show that the transcriptional regulation of the human LRAT gene is aberrant in human prostate cancer cells and that GATA transcription factors are involved in the transcriptional activation of LRAT in PrEC cells...
  9. pmc Homeostasis of retinol in lecithin: retinol acyltransferase gene knockout mice fed a high retinol diet
    Limin Liu
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
    Biochem Pharmacol 75:2316-24. 2008
    ..We show that LRAT plays a role in maintaining a stable serum retinol concentration when dietary retinol concentration fluctuates...
  10. ncbi Phase 1 trial of O6-benzylguanine and BCNU in children with CNS tumors: a Children's Oncology Group study
    Denise M Adams
    Cincinnati Children s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
    Pediatr Blood Cancer 50:549-53. 2008
    ....
  11. ncbi Cell proliferation inhibition and alterations in retinol esterification induced by phytanic acid and docosahexaenoic acid
    Xiao Han Tang
    Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA
    J Lipid Res 48:165-76. 2007
    ..In addition, we demonstrate that retinyl phytanate was generated by LRAT in the presence of PA and retinol; however, retinyl docosahexaenoate was produced by another enzyme in the presence of DHA and retinol...
  12. ncbi Reduced lecithin:retinol acyltransferase expression in human breast cancer
    Marni Sheren-Manoff
    Division of Hematology and Medical Oncology, New York Presbyterian Hospital Weill Cornell Medical Center, New York, NY 10021, USA
    Int J Oncol 29:1193-9. 2006
    ..Furthermore, normal human breast epithelium exhibits intense LRAT staining, indicating a major role for LRAT in human breast physiology...
  13. ncbi Structure elucidation of retinoids in biological samples using postsource decay laser desorption/ionization mass spectrometry after high-performance liquid chromatography separation
    Moo Jin Suh
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA
    Anal Chem 78:5719-28. 2006
    ..We show that the PSD-LDI MS approach described here can facilitate the identification and characterization of retinoids from mammalian cells and tissues...
  14. ncbi Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder
    Jay D Raman
    Department of Urology, The New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York 10021, USA
    Clin Cancer Res 11:8570-6. 2005
    ..We evaluated EZH2 mRNA and protein expression in bladder specimens from patients and the EZH2 mRNA expression in five bladder cancer cell lines...
  15. ncbi Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency
    Limin Liu
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA
    J Biol Chem 280:40226-34. 2005
    ....