Targeting Valine Catabolism for Selective Inhibition of Metabolic Reprogramming in Prostate Cancer

Metabolic reprogramming and energetic rewiring are hallmarks of cancer which fuel disease progression and facilitate evasion to the rising anti-tumour pressures introduced by therapy. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade PCa tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipids in PCa. Overall design: To investigate the global transcriptomic implications of valine catabolism inhibition on LNCaP prostate cancer cells by siRNA knockdown of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH).