TY - JOUR
T1 - The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D 3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells
AU - Myrthue, Anne
AU - Rademacher, Brooks L.S.
AU - Pittsenbarger, Janet
AU - Kutyba-Brooks, Bozena
AU - Gantner, Marin
AU - Qian, David Z.
AU - Beer, Tomasz M.
PY - 2008/6/1
Y1 - 2008/6/1
N2 - 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active metabolite of vitamin D3, has significant antitumor activity in a broad range of preclinical models of cancer. In this study, we show that the Iroquois homeobox gene 5 (Ir×5) is down-regulated by 1,25(OH)2D3 in human prostate cancer samples from patients randomly assigned to receive weekly high-dose 1,25(OH)2D3 or placebo before radical prostatectomy. Down-regulation of Ir×5 by 1,25(OH)2D3 was also shown in the human androgen-sensitive prostate cancer cell line LNCaP and in estrogen-sensitive MCF-7 breast cancer cells. Knockdown of Ir×5 by RNA interference showed a significant reduction in LNCaP cell viability, which was accompanied by an increase in p21 protein expression, G2-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 Ir×5 knockdown. Cell survival was similarly reduced by Ir×5 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)2D3. Overexpression of Ir×5 led to a reduction of p21 and p53 expression. This is the first report that Ir×5 is regulated by 1,25(OH)2D3 in humans and the first report to show that Ir×5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells. Ir×5 may be a promising new therapeutic target in cancer treatment.
AB - 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active metabolite of vitamin D3, has significant antitumor activity in a broad range of preclinical models of cancer. In this study, we show that the Iroquois homeobox gene 5 (Ir×5) is down-regulated by 1,25(OH)2D3 in human prostate cancer samples from patients randomly assigned to receive weekly high-dose 1,25(OH)2D3 or placebo before radical prostatectomy. Down-regulation of Ir×5 by 1,25(OH)2D3 was also shown in the human androgen-sensitive prostate cancer cell line LNCaP and in estrogen-sensitive MCF-7 breast cancer cells. Knockdown of Ir×5 by RNA interference showed a significant reduction in LNCaP cell viability, which was accompanied by an increase in p21 protein expression, G2-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 Ir×5 knockdown. Cell survival was similarly reduced by Ir×5 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)2D3. Overexpression of Ir×5 led to a reduction of p21 and p53 expression. This is the first report that Ir×5 is regulated by 1,25(OH)2D3 in humans and the first report to show that Ir×5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells. Ir×5 may be a promising new therapeutic target in cancer treatment.
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U2 - 10.1158/1078-0432.CCR-07-4649
DO - 10.1158/1078-0432.CCR-07-4649
M3 - Article
C2 - 18519790
AN - SCOPUS:50349097387
SN - 1078-0432
VL - 14
SP - 3562
EP - 3570
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -