Abstract 1132: Regulation of the glutamine-to-lipid pathway by HIF: Reductive TCA cycle is a metabolic signature of VHL deficiency

Abstract

Abstract Cancer cells undergo fundamental changes in glucose and glutamine metabolism to support anabolic processes. Acetyl-CoA is a central precursor for lipid synthesis, being generated from glucose-derived citrate in well oxygenated cells. Cells exposed to hypoxia divert glucose to lactate, raising the question of how TCA cycle is maintained to support lipogenesis. We recently showed that, under hypoxia conditions, cancer cells primarily utilize glutamine for lipid synthesis through reductive TCA cycle (redTCA). To investigate the regulation of this metabolic switch, we studied the role of Hypoxia Inducible Factors (HIF1s) in renal cell carcinoma (RCC) cell lines that are deficient in the von Hippel-Lindau (VHL) tumor suppressor gene. These cells exhibit constitutive HIF activity irrespective of oxygen availability. Here, we show that loss-of-VHL engages RCC cells in redTCA even under normoxia conditions in a HIF-dependent manner. Reintroduction of VHL restores the glucose-to-lipid flux. Inactivation of HIF regulatory subunits dramatically attenuates redTCA in RCC cell lines. Inversely, exogenous expression of a VHL-insensitive HIF2α mutant (P564toA) in VHL proficient cell lines is sufficient to stimulate redTCA cycle and lipogenesis from glutamine, under conditions of normoxia. Importantly, loss of VHL rendered RCC cells sensitive to glutamine restriction. VHL-deficient RCC cells grow less than their VHL-replete isogenic counterparts when cultured under conditions of low glutamine availability. Our results elucidate the metabolic control of lipogenesis by the VHL-HIF signaling pathway and highlight novel therapeutic targets for RCC and HIF-overexpressing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1132. doi:1538-7445.AM2012-1132