GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells.
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.
Flores
Omar
O
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, R-189, Room 6155 Rosenstiel Building, Miami, Florida 33136, USA.
Burnstein
Kerry L
KL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology* / Q000627:therapeutic use; D000097642:GADD45 Proteins
D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D054316:Biomarkers, Pharmacological; D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D014807:Vitamin D; C484017:ERRFI1 protein, human; C485654:GADD45G protein, human; D000097642:GADD45 Proteins