The Role of Hypoxia-Inducible Factor 1a in Determining the Properties of Castrate-Resistant Prostate Cancers

Background: Castrate-resistant prostate cancer (CRPC) is a lethal condition in patients receiving androgen deprivation therapy for prostate cancer (PC). Despite numerous studies showing the expression of HIF1a protein under normoxia in PC cell lines, the role of this normoxic HIF1a expression in chemo-resistance and migration has not been investigated previously. As no method is currently available to determine which tumors will progress to CRPC, the role of HIF1a in PC and its potential for predicting the development of CRPC was also investigated. Methods: The effect of HIF1a protein knockdown on chemo-resistance and migration of PC3 cells was assessed by cell counting and Transwell assays, respectively. Translation efficiency of HIF1a mRNA was determined in PC cells using a HIF1a 59UTR-luciferase construct. Clinical outcomes were correlated following the staining of 100 prostate tumors for HIF1a expression. Results: The CRPC-like cell lines (PC3 and DU145) expressed more HIF1a protein than an androgen sensitive cell line (LNCaP). Migration rate and chemo-resistance were higher in the PC3 cells and both were decreased when HIF1a expression was reduced. Increased translation of HIF1amRNA may be responsible for HIF1a overexpression in PC3 cells. Patients whose tumors expressed HIF1a had significantly decreased metastasis-free survival and the patients who were on androgen-deprivation therapy had decreased CRPC-free survival on Kaplan-Meier analysis. On multivariate analysis HIF1a was a