Historical rise of cancer and dietary linoleic acid: Mechanisms and therapeutic strategies

Figure 2 Linoleic acid-induced succinate build-up triggers pseudohypoxic hypoxia-inducible factor-1α stabilization and tumor-promoting glucose transporter type 1/vascular endothelial growth factor signaling. Excess β-oxidation of linoleic acid overloads succinate dehydrogenase, elevating mitochondrial succinate that inhibits prolyl-hydroxylase, thereby stabilizing hypoxia-inducible factor-1α despite normoxia (“pseudohypoxia”). The resulting transcription of glucose transporter type 1 and vascular endothelial growth factor supports glycolytic flux and neovascularization, hallmarks of aggressive tumor growth. LA: Linoleic acid; 4-HNE: 4-hydroxynonenal; OXLAMs: Oxidized linoleic acid metabolites; ROS: Reactive oxygen species; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells.