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1,25-Dihydroxyvitamin D₃ Reduces c-Myc Expression, Inhibiting Proliferation and Causing G₁ Accumulation in C4-2 Prostate Cancer Cells

Department of Molecular and Cellular Biology (J.N.P.R., N.L.W.) and Scott Department of Urology (N.L.W.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Nancy L. Weigel, Professor, Baylor College of Medicine, One Baylor Plaza, Mailstop M130, Houston, Texas 77030. E-mail: nweigel{at}bcm.edu.

There is an inverse correlation between exposure to sunlight (the major source of vitamin D) and the risk for prostate cancer, the most common noncutaneous cancer and second most common cause of death from cancer in American men. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] acting through the vitamin D receptor decreases prostate cancer cell growth and invasiveness. The precise mechanisms by which 1,25(OH)₂D₃ inhibits growth in prostate cancer have not been fully elucidated. Treatment with 1,25(OH)₂D₃ causes an accumulation in the G₀/G₁ phase of the cell cycle in several prostate cancer cell lines. One potential target known to regulate the G₀/G₁ to S phase transition is c-Myc, a transcription factor whose overexpression is associated with a number of cancers including prostate cancer. We find that 1,25(OH)₂D₃ reduces c-Myc expression in multiple prostate epithelial cell lines, including C4-2 cells, an androgen-independent prostate cancer cell line. Reducing c-Myc expression to the levels observed after 1,25(OH)₂D₃ treatment resulted in a comparable decrease in proliferation and G₁ accumulation demonstrating that down-regulation of c-Myc is a major component in the growth-inhibitory actions of 1,25(OH)2D₃. Treatment with 1,25(OH)₂D₃ resulted in a 50% decrease in c-Myc mRNA but a much more extensive reduction in c-Myc protein. Treatment with 1,25(OH)₂D₃ decreased c-Myc stability by increasing the proportion of c-Myc phosphorylated on T58, a glycogen synthase kinase-3β site that serves as a signal for ubiquitin-mediated proteolysis. Thus, 1,25(OH)₂D₃ reduces both c-Myc mRNA levels and c-Myc protein stability to inhibit growth of prostate cancer cells.