Inhibition of Intracellular Lipolysis Promotes Cancer Cell Adaptation to Hypoxia

摘要: Tumor tissues are chronically exposed to hypoxia owing aberrant vascularity. Lipid droplet (LD) accumulation is a hallmark of hypoxic cancer cells, yet how LDs form and function during remains poorly understood. Herein, we report that upon oxygen deprivation HIF-1 activation down-modulates LD catabolism mediated by adipose triglyceride lipase (ATGL), the key enzyme for intracellular lipolysis, in various cells. Proteomics functional analyses identified hypoxia-inducible gene 2 (HIG2), target, as new inhibitor ATGL. Knockout HIG2 enhanced breakdown fatty acid (FA) oxidation, leading increased ROS production apoptosis cells well impaired growth tumor xenografts. All these effects were reversed co-ablation Thus, inhibiting ATGL, acts downstream sequester FAs away from mitochondrial pathways oxidation generation, thereby sustaining cell survival hypoxia.