Increased expression of corepressors in aggressive androgen-independent prostate cancer cells results in loss of 1alpha,25-dihydroxyvitamin D3 responsiveness.
Vitamin D has antiproliferative activity in prostate cancer; however, resistance to vitamin D-mediated growth inhibition occurs. To investigate the mechanisms of vitamin D resistance, we screened two prostate cancer sublines of CWR22rv1, CWR22R-1, and CWR22R-2, with differential sensitivity to vitamin D. CWR22R-2 showed less response to the antiproliferative effect of vitamin D than CWR22R-1. The vitamin D receptor (VDR)-mediated transcriptional activity was also decreased in CWR22R-2. We further showed that the DNA-binding ability of VDR was decreased and the amount of NCoR in VDR response element was increased in CWR22R-2. Analysis of VDR-associated protein profiles found higher expression of the corepressors, NCoR1 and SMRT, in CWR22R-2 cells. Treatment with the histone deacetylase inhibitor, trichostatin A, increased vitamin D/VDR transcriptional activity and promoted the antiproliferative effect of vitamin D in CWR22R-2 cells. Targeted down-regulation of NCoR1 and SMRT by small interference RNA was able to restore CWR22R-2 response to vitamin D. Together, we showed that increased NCoR1 and SMRT expression in CWR22R-2 cells resulted in reduced VDR-mediated transcriptional activity and attenuated antiproliferative response to vitamin D. Our data suggest that the integrity of the vitamin D/VDR-mediated signaling pathway is crucial in predicting vitamin D responsiveness and thus provide a rational design to improve vitamin D-based treatment efficacy based on molecular profiles of patients.
Ting
Huei-Ju
HJ
Department of Urology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642, USA.
Bao
Bo-Ying
BY
Reeder
Jay E
JE
Messing
Edward M
EM
Lee
Yi-Fen
YF
D000728:Androgens / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D018167:Receptors, Calcitriol / Q000235:genetics; D015398:Signal Transduction
D000728:Androgens; D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D002117:Calcitriol; C078903:seocalcitol