期刊
BRITISH JOURNAL OF CANCER
卷 107, 期 10, 页码 1714-1721出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2012.455
关键词
hypoxia; RUNX2; Bcl-2; bicalutamide; prostate cancer; LNCaP
类别
资金
- Prostate Cancer Charity [110857]
- NIH [5P01CA140043]
BACKGROUND: We have previously shown that hypoxia selects for more invasive, apoptosis-resistant LNCaP prostate cancer cells, with upregulation 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. In addition, RUNX2-overexpressing 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 chromatin immunoprecipitation (ChIP) binding and reporter assays. Moreover, a Q-PCR array identified other apoptosis-associated genes upregulated in the RUNX2-overexpressing 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. British Journal of Cancer (2012) 107, 1714-1721. doi:10.1038/bjc.2012.455 www.bjcancer.com Published online 16 October 2012 (C) 2012 Cancer Research UK
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