The Enzymatic Activity of Apoptosis-inducing Factor Supports Energy Metabolism Benefiting the Growth and Invasiveness of Advanced Prostate Cancer Cells

Apoptosis-inducing factor (AIF) promotes cell death yet also controls mitochondrial homeostasis and energy metabolism. It is unclear how these activities are coordinated, and the impact of AIF upon human disease, in particular cancer, is not well documented. In this study we have explored the contribution of AIF to the progression of prostate cancer. Analysis of archival gene expression data demonstrated that AIF transcript levels are elevated in human prostate cancer, and we found that AIF protein is increased in prostate tumors. Suppression of AIF expression in the prostate cancer cell lines LNCaP, DU145, and PC3 demonstrated that AIF does not contribute to cell toxicity via a variety of chemical death triggers, and growth under nutrient-rich conditions is largely unaffected by AIF ablation. However, under growth stress conditions, AIF depletion from DU145 and PC3 cell lines led to significant reductions in cell survival and growth that were not observed in LNCaP cells. Moreover AIF-deficient PC3 cells exhibited substantial reduction of tumorigenic growth in vivo. This reduced survival correlated with decreased expression of mitochondrial complex I protein subunits and concomitant changes in glucose metabolism. Finally, restoration of AIF-deficient PC3 cells with AIF variants demonstrated that the enzymatic activity of AIF is required for aggressive growth. Overall these studies show that AIF is an important factor for advanced prostate cancer cells and that through control of energy metabolism and redox balance, the enzymatic activity of AIF is critical for this support.