GADD45γ: a New Vitamin D-Regulated Gene that Is Antiproliferative in Prostate Cancer Cells

摘要

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits proliferation of normal and malignant prostate epithelial cells at least in part through inhibition of G1 to S phase cell cycle progression. The mechanisms of the antiproliferative effects of 1,25-(OH)2D3 have yet to be fully elucidated but are known to require the vitamin D receptor. We previously developed a 1,25-(OH)2D3-resistant derivative of the human prostate cancer cell line, LNCaP, which retains active vitamin D receptors but is not growth inhibited by 1,25-(OH)2D3. Gene expression profiling revealed two novel 1,25-(OH)2D3-inducible genes, growth arrest and DNA damage-inducible gene gamma (GADD45γ) and mitogen induced gene 6 (MIG6), in LNCaP but not in 1,25-(OH)2D3-resistant cells. GADD45γ up-regulation was associated with growth inhibition by 1,25-(OH)2D3 in human prostate cancer cells. Ectopic expression of GADD45γ in either LNCaP or ALVA31 cells resulted in G₁ accumulation and inhibition of proliferation equal to or greater than that caused by 1,25-(OH)₂D₃ treatment. In contrast, ectopic expression of MIG6 had only minimal effects on cell cycle distribution and proliferation. Whereas GADD45γ has been shown to be induced by androgens in prostate cancer cells, up-regulation of GADD45γ by 1,25-(OH)₂D₃ was not dependent on androgen receptor signaling, further refuting a requirement for androgens/androgen receptor in vitamin D-mediated growth inhibition. These data introduce two novel 1,25-(OH)₂D₃-regulated genes and establish GADD45γ as a growth-inhibitory protein in prostate cancer. Furthermore, the induction of GADD45γ gene expression by 1,25-(OH)₂D₃ may mark therapeutic response in prostate cancer.