p53 Is required for 1,25-dihydroxyvitamin D3-induced G0 arrest but is not required for G1 accumulation or apoptosis of LNCaP prostate cancer cells.
1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is an effective agent for inhibiting the growth of prostate cancer cells including LNCaP and PC-3 cell lines. However, the extent of growth inhibition in these cell lines differs because LNCaP cells are much more responsive than PC-3 cells. Previous studies in LNCaP cells have shown that 1,25-(OH)(2)D(3) treatment results in G(0)/G(1) cell cycle accumulation, loss of Ki67 expression, and induction of apoptosis. One difference between the two cell lines is that PC-3 cells lack functional p53, a protein that plays roles both in cell cycle regulation and induction of apoptosis. In this study, the role of p53 in 1,25-(OH)(2)D(3) action was examined using the p53-negative PC-3 cells and a line of LNCaP cells, called LN-56, in which p53 function was shut off using a dominant negative p53 fragment. We found that treatment with 1,25-(OH)(2)D(3) extensively inhibits growth of LN-56 prostate cancer cells lacking p53, but in contrast to the parental LNCaP cells, the LN-56 cells recover rapidly. Moreover, in prostate cancer cells, the synergism between 1,25-(OH)(2)D(3) and 9-cis retinoic acid appears to be dependent on the presence of functional p53; however, 1,25-(OH)(2)D(3)-mediated induction of G(1) cell cycle accumulation and induction of apoptosis is not.
Polek
Tara C
TC
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Stewart
LaMonica V
LV
Ryu
Elizabeth J
EJ
Cohen
Michael B
MB
Allegretto
Elizabeth A
EA
Weigel
Nancy L
NL
D000077556:Alitretinoin; D017209:Apoptosis / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D000077556:Alitretinoin; D014212:Tretinoin; D002117:Calcitriol