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dc.contributor.advisorMiriam Falzon, Ph.D.en_US
dc.creatorVeronica Alejandra Tovar Sepulvedaen_US
dc.date.accessioned2011-12-20T16:04:59Z
dc.date.available2008-06-17en_US
dc.date.available2011-12-20T16:04:59Z
dc.date.created2005-07-20en_US
dc.date.issued2005-07-08en_US
dc.identifier.otheretd-07202005-151924en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/171
dc.description.abstractParathyroid hormone-related protein (PTHrP) is expressed by prostate cancer cells. Since PTHrP enhances the growth and osteolytic potential of prostate cancer cells, it is important to control PTHrP expression in these cells. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) downregulates PTHrP expression in a variety of human cell types, including prostate cancer cells. Therefore, downregulation of PTHrP gene expression by 1,25(OH)2D3 may enhance the therapeutic benefits of 1,25(OH)2D3 by neutralizing PTHrP’s contribution to the pathogenesis and progression of prostate carcinoma and its tendency to metastasize to bone. In this study, we show that 1,25(OH)2D3 and its non-hypercalcemic analog EB1089 decrease cell proliferation and suppress PTHrP mRNA and protein levels in the human prostate cancer cell lines LNCaP, C4-2, and PC-3. These cell lines represent early to advanced stages of prostate cancer, since LNCaP cells are weakly metastatic, androgen receptor (AR)-positive and androgen-responsive cells, C4-2 cells are AR-positive and androgen-independent LNCaP variants, and PC-3 cells are highly metastatic AR-negative cells. We identified a negative vitamin D response element (nVDREhPTHrP) within the human PTHrP gene; interaction of the vitamin D receptor (VDR) with this nVDRE is decreased by 1,25(OH)2D3. However, transient transfection of nVDREhPTHrP cloned upstream of the SV40 promoter downregulated promoter activity in response to 1,25(OH)2D3 or EB1089 treatment in LNCaP and C4-2, but not in PC-3, cells. The retinoid X receptor (RXR) is a frequent heterodimeric partner of the VDR. We show that RXRα forms part of the nuclear protein complex that interacts with nVDREhPTHrP with the VDR in LNCaP, C4-2, and PC-3 cells. The RXR ligand 9-cis-retinoic acid (9-cis-RA) downregulates PTHrP mRNA levels in both LNCaP and C4-2 cells; this decrease is more pronounced in LNCaP than in C4-2 cells. 9-cis-RA also enhances the 1,25(OH)2D3-mediated downregulation of PTHrP expression in both cell lines; this effect is more pronounced in LNCaP cells. Co-treatment with 1,25(OH)2D3 or EB1089 and 9-cis-RA further decreased promoter activity driven via nVDREhPTHrP in LNCaP, but not C4-2, cells. The proliferation of LNCaP, but not C4-2, cells is decreased by 9-cis-RA. These results indicate that PTHrP gene expression is regulated by 1,25(OH)2D3 in a cell line-specific manner in prostate cancer cells.en_US
dc.format.mediumelectronicen_US
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectvitamin D receptoren_US
dc.subjectretinoic X receptoren_US
dc.subjectparathyroid hormone related proteinen_US
dc.subjectnegative vitamin D response elementen_US
dc.subject25-dihydroxyvitamin D3en_US
dc.subject1en_US
dc.title“Differential regulation of PTHrP gene expression by 1,25(OH)2D3 in prostate cancer cell lines”en_US
dc.type.materialtexten_US
dc.type.genredissertationen_US
thesis.degree.namePhDen_US
thesis.degree.levelDoctoralen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.departmentPharmacology and Toxicologyen_US
dc.contributor.committeeMemberNancy L. Weigel, Ph.D.en_US
dc.contributor.committeeMemberMelvin S. Soloff, Ph.D.en_US
dc.contributor.committeeMemberMary L. Thomas, Ph.D.en_US
dc.contributor.committeeMemberCheryl S. Watson, Ph.D.en_US
dc.contributor.committeeMemberCary W. Cooper, Ph.D.en_US


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