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

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Browne, G, Nesbitt, H, Ming, L, Stein, GS, Lian, JB, McKeown, SR and Worthington, Jenny (2012) Bicalutamide-induced hypoxia potentiates RUNX2-mediated Bcl-2 expression resulting in apoptosis resistance. British Journal of Cancer, 107 . pp. 1714-1721. [Journal article]

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DOI: 10.1038/bjc.2012.455.

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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Molecular Medicine
Institute of Nursing and Health Research > Centre for Health and Rehabilitation Technologies
ID Code:24196
Deposited By:Dr Jenny Worthington
Deposited On:27 Nov 2012 09:37
Last Modified:27 Nov 2012 09:37

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