Effect of a HIF-1 Alpha Polymorphism on the Incidence and Prostate Cancer
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2008
- Accession Number
- ADA482658
Entities
People
- Glen Bubley
Organizations
- Beth Israel Deaconess Medical Center