Hypoxia-inducible factor 1α: A screening tool for predicting development of castrate resistant prostate cancer.

Abstract

e15117 Background: Currently there is no method to determine which patients starting androgen deprivation therapy (ADT) for prostate cancer (PC) will progress to castrate resistant prostate cancer (CRPC) while the reasons for early metastases and chemoresistance in CRPCs are unknown. We aimed to investigate the potential role of hypoxia inducible factor 1α (HIF1α), a key transcription factor in the cell mediated adaptive response to changes in tissue oxygenation, in predicting the development of CRPC. Methods: 100 prostate tumour samples were divided into Gleason ≤7 (38) and Gleason >7 (62) and stained for HIF1α using immunohistochemistry, blinded to the outcomes. The outcomes of CRPC, metastases and PC specific death were measured and correlated with HIF1α expression. In vitro, the effects of HIF1α on proliferation, survival and migration of PC cells were assessed by cell count and Boyden chamber assays. Results: HIF1α expression in PC was independent of Gleason grade and tumour stage. HIF1α was an independent risk factor for development of CRPC (Hazard Ratio (HR) 10.4), progression to metastases (HR 9.8) and PC specific death (HR 13.4) at median times of 23, 24 and 25 months respectively, from the start of ADT on a multivariate Cox regression analysis (all p<0.05) adjusted for Gleason score, PSA and age. CRPC free survival, metastases free survival and PC specific survival were all significantly decreased in patients with HIF1α on Kaplan Meier analyses. The presence of HIF1α was highly sensitive (all 100%) with excellent negative predictive values (all 100%) for all 3 outcomes, but had poor specificity. HIF1α over-expressing PC3 cells (CRPC) were compared with androgen sensitive LNCaP cells in vitro. PC3 cells were resistant to cytotoxic agents including H2O2 (oxidative stress) and 5-fluorouracil (chemotherapy agent) and had higher rates of migration compared to LNCaP cells. HIF1α knockdown in PC3 cells reversed these effects. Protein translation efficiency in PC3 cells was significantly higher than LNCaP cells. Conclusions: HIF1α is a good screening tool for CRPC. HIF1α expression is likely to contribute to metastases and chemoresistance of CRPCs and is likely upregulated at protein translation in PC cells.