Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance.

G Browne, H Nesbitt, L Ming, GS Stein, JB Lian, SR McKeown, Jenny Worthington

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    Abstract

    Background: We have previously shown that hypoxia selects for more invasive, apoptosis-resistant LNCaP prostate cancer cells, with up-regulation of the osteogenic transcription factor RUNX2 and the anti-apoptotic factor Bcl-2 detected in the hypoxia-selected cells. Following this observation we questioned through what biological mechanism this occurs. Methods: We examined the effect of hypoxia on RUNX2 expression and the role of RUNX2 in the regulation of Bcl-2 and apoptosis resistance in prostate cancer. Results: Hypoxia increased RUNX2 expression in vitro and bicalutamide-treated LNCaP tumours in mice (previously shown to have increased tumour hypoxia) exhibited increased RUNX2 expression. Additionally, RUNX2 over-expressing LNCaP cells showed increased cell viability following bicalutamide and docetaxel treatment which was inhibited by RUNX2 siRNA; a range of assays demonstrated that this was due to resistance to apoptosis. RUNX2 expression was associated with increased Bcl-2 levels, and regulation of Bcl-2 by RUNX2 was confirmed through ChIP binding and reporter assays. Moreover, a Q-PCR array identified other apoptosis-associated genes up-regulated in the RUNX2 over-expressing LNCaP cells. Conclusion: This study establishes a contributing mechanism for progression of prostate cancer cells to a more apoptosis-resistant and thus malignant phenotype, whereby increased expression of RUNX2 modulates the expression of apoptosis-associated factors, specifically Bcl-2.
    LanguageEnglish
    Pages1714-1721
    JournalBRITISH JOURNAL OF CANCER
    Volume107
    DOIs
    Publication statusPublished - 2012

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    Apoptosis
    Prostatic Neoplasms
    docetaxel
    Cell Hypoxia
    Small Interfering RNA
    bicalutamide
    Hypoxia
    Cell Survival
    Transcription Factors
    Up-Regulation
    Phenotype
    Polymerase Chain Reaction
    Genes
    Neoplasms

    Cite this

    Browne, G., Nesbitt, H., Ming, L., Stein, GS., Lian, JB., McKeown, SR., & Worthington, J. (2012). Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance. BRITISH JOURNAL OF CANCER, 107, 1714-1721. https://doi.org/10.1038/bjc.2012.455.
    Browne, G ; Nesbitt, H ; Ming, L ; Stein, GS ; Lian, JB ; McKeown, SR ; Worthington, Jenny. / Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance. In: BRITISH JOURNAL OF CANCER. 2012 ; Vol. 107. pp. 1714-1721.
    @article{3ba15b734835478d9c5688dfe9535ba6,
    title = "Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance.",
    abstract = "Background: We have previously shown that hypoxia selects for more invasive, apoptosis-resistant LNCaP prostate cancer cells, with up-regulation of the osteogenic transcription factor RUNX2 and the anti-apoptotic factor Bcl-2 detected in the hypoxia-selected cells. Following this observation we questioned through what biological mechanism this occurs. Methods: We examined the effect of hypoxia on RUNX2 expression and the role of RUNX2 in the regulation of Bcl-2 and apoptosis resistance in prostate cancer. Results: Hypoxia increased RUNX2 expression in vitro and bicalutamide-treated LNCaP tumours in mice (previously shown to have increased tumour hypoxia) exhibited increased RUNX2 expression. Additionally, RUNX2 over-expressing LNCaP cells showed increased cell viability following bicalutamide and docetaxel treatment which was inhibited by RUNX2 siRNA; a range of assays demonstrated that this was due to resistance to apoptosis. RUNX2 expression was associated with increased Bcl-2 levels, and regulation of Bcl-2 by RUNX2 was confirmed through ChIP binding and reporter assays. Moreover, a Q-PCR array identified other apoptosis-associated genes up-regulated in the RUNX2 over-expressing LNCaP cells. Conclusion: This study establishes a contributing mechanism for progression of prostate cancer cells to a more apoptosis-resistant and thus malignant phenotype, whereby increased expression of RUNX2 modulates the expression of apoptosis-associated factors, specifically Bcl-2.",
    author = "G Browne and H Nesbitt and L Ming and GS Stein and JB Lian and SR McKeown and Jenny Worthington",
    year = "2012",
    doi = "10.1038/bjc.2012.455.",
    language = "English",
    volume = "107",
    pages = "1714--1721",
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    Browne, G, Nesbitt, H, Ming, L, Stein, GS, Lian, JB, McKeown, SR & Worthington, J 2012, 'Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance.', BRITISH JOURNAL OF CANCER, vol. 107, pp. 1714-1721. https://doi.org/10.1038/bjc.2012.455.

    Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance. / Browne, G; Nesbitt, H; Ming, L; Stein, GS; Lian, JB; McKeown, SR; Worthington, Jenny.

    In: BRITISH JOURNAL OF CANCER, Vol. 107, 2012, p. 1714-1721.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance.

    AU - Browne, G

    AU - Nesbitt, H

    AU - Ming, L

    AU - Stein, GS

    AU - Lian, JB

    AU - McKeown, SR

    AU - Worthington, Jenny

    PY - 2012

    Y1 - 2012

    N2 - Background: We have previously shown that hypoxia selects for more invasive, apoptosis-resistant LNCaP prostate cancer cells, with up-regulation of the osteogenic transcription factor RUNX2 and the anti-apoptotic factor Bcl-2 detected in the hypoxia-selected cells. Following this observation we questioned through what biological mechanism this occurs. Methods: We examined the effect of hypoxia on RUNX2 expression and the role of RUNX2 in the regulation of Bcl-2 and apoptosis resistance in prostate cancer. Results: Hypoxia increased RUNX2 expression in vitro and bicalutamide-treated LNCaP tumours in mice (previously shown to have increased tumour hypoxia) exhibited increased RUNX2 expression. Additionally, RUNX2 over-expressing LNCaP cells showed increased cell viability following bicalutamide and docetaxel treatment which was inhibited by RUNX2 siRNA; a range of assays demonstrated that this was due to resistance to apoptosis. RUNX2 expression was associated with increased Bcl-2 levels, and regulation of Bcl-2 by RUNX2 was confirmed through ChIP binding and reporter assays. Moreover, a Q-PCR array identified other apoptosis-associated genes up-regulated in the RUNX2 over-expressing LNCaP cells. Conclusion: This study establishes a contributing mechanism for progression of prostate cancer cells to a more apoptosis-resistant and thus malignant phenotype, whereby increased expression of RUNX2 modulates the expression of apoptosis-associated factors, specifically Bcl-2.

    AB - Background: We have previously shown that hypoxia selects for more invasive, apoptosis-resistant LNCaP prostate cancer cells, with up-regulation of the osteogenic transcription factor RUNX2 and the anti-apoptotic factor Bcl-2 detected in the hypoxia-selected cells. Following this observation we questioned through what biological mechanism this occurs. Methods: We examined the effect of hypoxia on RUNX2 expression and the role of RUNX2 in the regulation of Bcl-2 and apoptosis resistance in prostate cancer. Results: Hypoxia increased RUNX2 expression in vitro and bicalutamide-treated LNCaP tumours in mice (previously shown to have increased tumour hypoxia) exhibited increased RUNX2 expression. Additionally, RUNX2 over-expressing LNCaP cells showed increased cell viability following bicalutamide and docetaxel treatment which was inhibited by RUNX2 siRNA; a range of assays demonstrated that this was due to resistance to apoptosis. RUNX2 expression was associated with increased Bcl-2 levels, and regulation of Bcl-2 by RUNX2 was confirmed through ChIP binding and reporter assays. Moreover, a Q-PCR array identified other apoptosis-associated genes up-regulated in the RUNX2 over-expressing LNCaP cells. Conclusion: This study establishes a contributing mechanism for progression of prostate cancer cells to a more apoptosis-resistant and thus malignant phenotype, whereby increased expression of RUNX2 modulates the expression of apoptosis-associated factors, specifically Bcl-2.

    U2 - 10.1038/bjc.2012.455.

    DO - 10.1038/bjc.2012.455.

    M3 - Article

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    T2 - BRITISH JOURNAL OF CANCER

    JF - BRITISH JOURNAL OF CANCER

    SN - 0007-0920

    ER -