“Differential regulation of PTHrP gene expression by 1,25(OH)2D3 in prostate cancer cell lines”

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Title: “Differential regulation of PTHrP gene expression by 1,25(OH)2D3 in prostate cancer cell lines”
Author: Veronica Alejandra Tovar Sepulveda
Abstract: Parathyroid 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 RXR & #945 ; 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 .
URI: http : / /hdl .handle .net /2152 .3 /171
Date: 2005-07-08

Citation

“Differential regulation of PTHrP gene expression by 1,25(OH)2D3 in prostate cancer cell lines”. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /171 .

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