The Iroquois Homeobox Gene 5 Is Regulated by 1,25-Dihydroxyvitamin D3 in Human Prostate Cancer and Regulates Apoptosis and the Cell Cycle in LNCaP Prostate Cancer Cells

• Published in: Clinical cancer research 2008-06, Vol.14 (11), p.3562-3570
• Main Authors: MYRTHUE, Anne, RADEMACHER, Brooks L. S, PITTSENBARGER, Janet, KUTYBA-BROOKS, Bozena, GANTNER, Marin, QIAN, David Z, BEER, Tomasz M
• Format: Article
• Language: English
• Subjects: 1,25-dihydroxyvitamin D; Antineoplastic agents; Apoptosis - genetics; Biological and medical sciences; Blotting, Western; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; calcitriol; Calcitriol - pharmacology; Cell Cycle - genetics; Cell Line, Tumor; colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Down-Regulation; Female; Gene Expression Regulation; Gynecology. Andrology. Obstetrics; Homeodomain Proteins - drug effects; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Irx5; Male; Male genital diseases; Medical sciences; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Randomized Controlled Trials as Topic; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transcription Factors - drug effects; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - drug effects; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Vitamins - pharmacology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4649

1,25-Dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the most active metabolite of vitamin D 3 , has significant antitumor activity in a broad range of preclinical models of cancer. In this study, we show that the Iroquois homeobox gene 5 ( Irx5 ) is down-regulated by 1,25(OH) 2 D 3 in human prostate cancer samples from patients randomly assigned to receive weekly high-dose 1,25(OH) 2 D 3 or placebo before radical prostatectomy. Down-regulation of Irx5 by 1,25(OH) 2 D 3 was also shown in the human androgen-sensitive prostate cancer cell line LNCaP and in estrogen-sensitive MCF-7 breast cancer cells. Knockdown of Irx5 by RNA interference showed a significant reduction in LNCaP cell viability, which was accompanied by an increase in p21 protein expression, G 2 -M arrest, and an increase in apoptosis. The induced apoptosis was partially mediated by p53, and p53 protein expression was increased as a result of Irx5 knockdown. Cell survival was similarly reduced by Irx5 knockdown in the colon cancer cell line HCT 116 and in MCF-7 breast cancer cells, each being derived from clinical tumor types that seem to be inhibited by 1,25(OH) 2 D 3 . Overexpression of Irx5 led to a reduction of p21 and p53 expression. This is the first report that Irx5 is regulated by 1,25(OH) 2 D 3 in humans and the first report to show that Irx5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells. Irx5 may be a promising new therapeutic target in cancer treatment.