Growth inhibitory effects of 1alpha, 25-dihydroxyvitamin D(3) are mediated by increased levels of p21 in the prostatic carcinoma cell line ALVA-31.
1alpha, 25-Dihydroxyvitamin D(3) [1alpha, 25-(OH)(2)D(3)] is recognized to have significant antiproliferative effects on certain prostatic carcinoma (PC) cell lines, although the precise mechanisms of action remain in question. We have evaluated the role of the cell cycle-dependent kinase inhibitor p21. In the PC cell lines ALVA-31 and LNCaP, 1alpha, 25-(OH)(2)D(3) inhibits growth and induces both p21 mRNA and protein levels. Growth inhibition of ALVA-31 cells was abolished by stable transfection with a p21 antisense construct. This effect was not attributable to a reduction in functional vitamin D receptors as measured by transcriptional activity with a luciferase-vitamin D response element reporter construct. Therefore, increased p21 expression appears necessary to mediate the antiproliferative effects of this hormone in ALVA-31 cells. Cell lines that are insensitive to the growth inhibitory properties of 1alpha, 25-(OH)(2)D(3) failed to up-regulate p21 expression after hormone treatment; these include sublines of ALVA-31 as well as the cell lines TSU-Pr1 and JCA-1. In the latter two lines, adenovirus-mediated expression of a sense p21 cDNA significantly reduced their proliferation as compared with a control adenoviral construct. This suggests that the signaling pathway downstream of p21 is intact in TSU-Pr1 and JCA-1 cells, although p21 expression appears unregulated by 1alpha, 25-(OH)(2)D(3). We propose a model in which the antiproliferative effect of 1alpha, 25-(OH)(2)D(3) on PC cells is mediated through increased p21 expression. Elucidation of why this effect is absent in select cell lines may provide valuable insight into the variability of responses observed in PC patients treated with vitamin D.
Moffatt
K A
KA
University of Colorado Health Sciences Center, Department of Pathology, Denver, Colorado 80262, USA.
Johannes
W U
WU
Hedlund
T E
TE
Miller
G J
GJ
D002117:Calcitriol / Q000494:pharmacology*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D016373:DNA, Antisense / Q000235:genetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016373:DNA, Antisense; D006131:Growth Inhibitors; D002117:Calcitriol