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The role of HIF-1 in the apoptotic response of prostate cancer cells to hypoxia
The role of HIF-1 in the apoptotic
response
of prostate cancer cells to hypoxia.
Ronan N.T. Coffey, R. William G. Watson, Helmut Klocker, John M. Fitzpatrick, Department of Surgery, Mater Misericordiae University Hospital, Conway Institute, University College Dublin, Dublin, Ireland and Department of Urology, University of Innsbruck, Innsbruck, Austria. Introduction: The ability of cancer cells to adapt to hypoxia is critical for tumour growth. Hypoxia is known to exist in tumours and has been associated with poor prognosis. Hypoxic inducible factor-l (HIF1) is a transcription factor that regulates genes associated with adaptation to reduced oxygen pressure. Increased expression of HIF-1 has been found in the majority of prostate tumours. The aim of this study was to correlate HIF-1 expression to a resistance to hypoxia induced apoptosis in a series of prostate cell lines. Material and Methods: Expression of HIF-la was determined by Western blotting on nuclear isolates of cells cultured over a 72 hr period under 1%02. HIF-1 activity was determined through the use of specific reporter plasmids containing hypoxic response elements (HRE) in the promoter regions. Results: Results showed that all of the cell lines displayed a time-dependent increase in HIF-1 nuclear expression with hypoxia and that this increase in nuclear expression correlated to an increase in HIF-1 activity. Notably the androgen resistant PC-3 cell line displayed constitutive higher levels of HIF-1 activation compared to the androgen sensitive LNCaP cell line which may explain why the PC-3 cell line is resistant to hypoxia induced apoptosis. Interestingly the androgen insensitive LNCaP-hof and LNCaP-abl sublines were resistant to hypoxia-induced apoptosis despite displaying the same level of HIF-1 activation as the parental LNCaP line. Conclusion: This suggests that either HIF-1 is capable of mediating a survival signaling pathway specifically in the sublines or that resistance to hypoxia-induced apoptosis is a result of some other survival signaling pathway.
response
of prostate cancer cells to hypoxia.
Ronan N.T. Coffey, R. William G. Watson, Helmut Klocker, John M. Fitzpatrick, Department of Surgery, Mater Misericordiae University Hospital, Conway Institute, University College Dublin, Dublin, Ireland and Department of Urology, University of Innsbruck, Innsbruck, Austria. Introduction: The ability of cancer cells to adapt to hypoxia is critical for tumour growth. Hypoxia is known to exist in tumours and has been associated with poor prognosis. Hypoxic inducible factor-l (HIF1) is a transcription factor that regulates genes associated with adaptation to reduced oxygen pressure. Increased expression of HIF-1 has been found in the majority of prostate tumours. The aim of this study was to correlate HIF-1 expression to a resistance to hypoxia induced apoptosis in a series of prostate cell lines. Material and Methods: Expression of HIF-la was determined by Western blotting on nuclear isolates of cells cultured over a 72 hr period under 1%02. HIF-1 activity was determined through the use of specific reporter plasmids containing hypoxic response elements (HRE) in the promoter regions. Results: Results showed that all of the cell lines displayed a time-dependent increase in HIF-1 nuclear expression with hypoxia and that this increase in nuclear expression correlated to an increase in HIF-1 activity. Notably the androgen resistant PC-3 cell line displayed constitutive higher levels of HIF-1 activation compared to the androgen sensitive LNCaP cell line which may explain why the PC-3 cell line is resistant to hypoxia induced apoptosis. Interestingly the androgen insensitive LNCaP-hof and LNCaP-abl sublines were resistant to hypoxia-induced apoptosis despite displaying the same level of HIF-1 activation as the parental LNCaP line. Conclusion: This suggests that either HIF-1 is capable of mediating a survival signaling pathway specifically in the sublines or that resistance to hypoxia-induced apoptosis is a result of some other survival signaling pathway.