Nitric Oxide Up-Regulates RUNX2 in LNCaP Prostate Tumours: Implications for Tumour Growth In Vitro and In Vivo
BACKGROUND: Aberrant expression of the transcription factor RUNX2 in prostate cancer has a number of important consequences including increased resistance to apoptosis, invasion and metastasis to bone. We previously demonstrated that hypoxia up-regulated RUNX2 in tumour cells, which in turn up-regulated the anti-apoptotic factor Bcl-2. Here, we investigate the impact of nitric oxide (NO) on RUNX2 and Bcl-2 expression in prostate cancer and further, how RUNX2 over-expression can impact tumour growth, angiogenesis and oxygenation in vivo. METHODS: The effect of NO levels on RUNX2 and thus Bcl-2 expression was examined in prostate cancer cells in vitro using methods including gene and protein expression analyses, nitrite quantitation, protein-DNA interaction assays (ChIP) and viability assays (XTT). The effect of RUNX2 over-expression on tumour physiology (growth, oxygenation and angiogenesis) was also assessed in vivo using LNCaP xenografts. RESULTS: A low (but not high) concentration of NO (10microM) induced expression of RUNX2 and Bcl-2, conferring resistance to docetaxel. These effects were induced via the ERK and PI3K pathways and were dependent on intact AP-1 binding sites in the RUNX2 promoter. RUNX2 over-expression in LNCaP tumours in vivo decreased the time to tumour presentation and increased tumour growth. Moreover, these tumours exhibited improved tumour angiogenesis and oxygenation. CONCLUSION: Low levels of NO increase expression of RUNX2 and Bcl-2 in LNCaP prostate tumour cells, and in vivo up-regulation of RUNX2 created tumours with a more malignant phenotype. Collectively, our data reveals the importance of NO-regulation of key factors in prostate cancer disease progression. This article is protected by copyright. All rights reserved.
|ISBN||1097-4652 (Electronic) 0021-9541 (Linking)|
|Authors||Nesbitt, H.; Browne, G.; O'Donovan, K. M.; Byrne, N. M.; Worthington, J.; McKeown, S. R.; McKenna, D. J.;|
|Responsible Garvan Author|
|Publisher Name||JOURNAL OF CELLULAR PHYSIOLOGY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26189652|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13244|