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1α,25‐dihydroxyvitamin D 3 inhibits C4‐2 prostate cancer cell growth via a retinoblastoma protein (Rb)‐independent G 1 arrest
Author(s) -
Washington Michele N.,
Kim JungSun,
Weigel Nancy L.
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21226
Subject(s) - prostate cancer , e2f , retinoblastoma , cancer research , prostate , retinoblastoma protein , regulator , cell growth , biology , cell cycle , transcription factor , medicine , endocrinology , cancer , chemistry , gene , biochemistry
BACKGROUND The active metabolite of vitamin D, 1α,25‐dihydroxyvitamin D 3 (1,25D) reduces the growth of several prostate cancer cell lines, most commonly by inducing a cell‐cycle arrest in G 1 . This is mediated, in part, through down‐regulation of c‐Myc, a positive regulator of the transcription factor, E2F. There is evidence that prostate cancer cells lacking functional retinoblastoma protein (Rb), a negative regulator of E2F activity, are poorly responsive to 1,25D treatment. Since up to 60% of prostate cancers demonstrate a loss of heterozygosity for Rb, we sought to determine whether Rb is required for the growth inhibitory effects of 1,25D. METHODS Using siRNA, Rb was reduced in C4‐2 prostate cancer cells, and the response of cells to 1,25D treatment or depletion of c‐myc measured by [ 3 H]‐thymidine incorporation and flow cytometry. The effects of 1,25D treatment on E2F levels and activity, and E2F target gene expression were also measured. RESULTS 1,25D treatment and c‐Myc depletion both cause a G 1 arrest inhibiting C4‐2 cell proliferation independently of Rb. 1,25D reduces c‐Myc expression and causes a decrease in E2F and E2F target genes. Bcl‐2, an E2F target and positive regulator of C4‐2 cell growth, also is down‐regulated by 1,25D independently of Rb. CONCLUSIONS Redundant growth inhibitory pathways compensate for the loss of Rb, and tumors lacking functional Rb may be responsive to 1,25D. Prostate 71: 98–110, 2011. © 2010 Wiley‐Liss, Inc.