In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4009-4009
Abstract:
Hypoxia is known to act as a selective pressure in the tumor microenvironment, often resulting in sub-populations of cells that have a propensity for more aggressive behaviour. More recently, Runx2 (an osteogenic transcription factor) has been associated with tumor growth, invasion and metastasis. Previous results in our laboratory have indicated that hypoxia selects for more invasive, apoptosis-resistant prostate cancer cells. Microarray analysis revealed that both Runx2 and Bcl-2 (an anti-apoptotic protein) were up-regulated in the hypoxia-selected cells (Butterworth et al, 2008). Bcl-2 is known to be up-regulated in various malignancies, and is associated with more aggressive disease and resistance to chemotherapy. Subsequent analysis of the Bcl-2 promoter revealed two binding sites for Runx2. In the current study we confirmed regulation of Bcl-2 by Runx2 though ChIP binding and reporter assays in LNCaP prostate cancer cells. Runx2 over-expressing LNCaP cells showed increased cell viability which was inhibited by Runx2 siRNA knockdown. A variety of assays demonstrated that Runx2 over-expressing cells were more resistant to apoptosis than controls. We further addressed the effect of hypoxia on Runx2 expression and the potential role Runx2 might play in the regulation of Bcl-2 expression and thus apoptosis in prostate cancer. When LNCaP cells were exposed to hypoxia, both Runx2 and Bcl-2 mRNA and protein levels were significantly increased over oxic controls. In a separate in vivo study, treatment of LNCaP tumors grown on the backs of immuno-compromised mice with the anti-androgen bicalutamide resulted in a profound decrease in tumor oxygenation during the first 14 days. Over the following 14 days, oxygen levels gradually increased. Further investigation of the excised tumors showed an increase in Runx2 mRNA levels from day 7, which was further confirmed by western and immunohistochemical analyses. In summary, this study shows that hypoxia promotes over-expression of Runx2 in prostate cancer cells. The cells exhibit a survival advantage through up-regulation of Bcl-2 leading to apoptosis resistance. These results, taken together with the in vivo data, suggest that Runx2 expression (either through microenvironmental pressures or ectopic expression) promotes progression to a more apoptosis-resistant and thus malignant phenotype, highlighting Runx2 as a potential therapeutic target in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4009. doi:1538-7445.AM2012-4009
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-4009
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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