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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

Department of Molecular and Cellular Biology (T.C.P., L.V.S., E.J.R., N.L.W.), Baylor College of Medicine, Houston, Texas 77030; Department of Pathology, Urology, and Epidemiology (M.B.C), University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52242; and Ligand Pharmaceuticals, Inc. (E.A.A.), San Diego, California 92121

Address all correspondence and requests for reprints to: Dr. Nancy L. Weigel, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. E-mail: nweigel{at}bcm.tmc.edu.

1,25-Dihydroxyvitamin D₃ [1,25-(OH)₂D₃] 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)₂D₃ treatment results in G₀/G₁ 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)₂D₃ 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)₂D₃ 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)₂D₃ and 9-cis retinoic acid appears to be dependent on the presence of functional p53; however, 1,25-(OH)₂D₃-mediated induction of G₁ cell cycle accumulation and induction of apoptosis is not.

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