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

Anne Myrthue, Brooks L S Rademacher, Janet Pittsenbarger, Bozena Kutyba-Brooks, Marin Gantner, Zheng (David) Qian, Tomasz (Tom) Beer

    Research output: Contribution to journalArticle

    45 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)3562-3570
    Number of pages9
    JournalClinical Cancer Research
    Volume14
    Issue number11
    DOIs
    StatePublished - Jun 1 2008

    Fingerprint

    Homeobox Genes
    Prostatic Neoplasms
    Cell Cycle
    Apoptosis
    Cell Survival
    Breast Neoplasms
    Cell Line
    Neoplasms
    Calcitriol
    Cholecalciferol
    Prostatectomy
    RNA Interference
    Colonic Neoplasms
    Androgens
    Estrogens
    Proteins
    Down-Regulation
    Placebos
    1,25-dihydroxyvitamin D
    Therapeutics

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    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. / Myrthue, Anne; Rademacher, Brooks L S; Pittsenbarger, Janet; Kutyba-Brooks, Bozena; Gantner, Marin; Qian, Zheng (David); Beer, Tomasz (Tom).

    In: Clinical Cancer Research, Vol. 14, No. 11, 01.06.2008, p. 3562-3570.

    Research output: Contribution to journalArticle

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    abstract = "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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    AU - Beer, Tomasz (Tom)

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