Effect of a HIF-1 Alpha Polymorphism on the Incidence and Prostate Cancer
Final rept. 7 Jan 2007-6 Jan 2008
BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
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The P582S C-T and A588T G-A polymorphisms in the Hypoxia-inducible factor-1alpha HIF-1alpha gene have been associated with enhanced stability of the protein and androgen-independent prostate cancer CaP During the course of our research we published that P582S polymorphism was not associated with CaP see appendix. However we observed a significant interaction of the P582S genotype with insulin-like growth factor binding protein IGFBP-3 in modifying CaP risk such that higher IGFBP-3 levels versus median were associated with a reduced risk only among men with the wildtype OR, 95 CI 0.74, 0.57-0.97 Pinteraction 0.01. We therefore went on in the final year to study the effect of HIF 1 translation after treatment with agents that might down regulate IGF-1 down-stream signaling. Methods Prostate cancer cell lines were treated with rapamycin, an mTOR antagonist, and the effect on HIF-1 protein levels was studied. Results We found that agents such as rapamycin that might down regulate the effect of IGF-1 signaling by inhibiting the mTOR pathway, paradoxically increased HIF 1 protein levels. Conclusions Treatment of prostate cancer with agents that attempt to affect signal transduction can have a paradoxical effect of HIF-1 protein levels by affecting its translation.
- Medicine and Medical Research