Disrupting the ‘Warburg effect’ re-routes cancer cells to OXPHOS offering a vulnerability point via ‘ferroptosis’-induced cell death

The evolution of life from extreme hypoxic environments to an oxygen-rich atmosphere has progressively selected for successful metabolic, enzymatic and bioenergetic networks through which a myriad of organisms survive the most extreme environmental conditions. From the two lethal environments anoxia/high O2, cells have developed survival strategies through expression of the transcriptional factors ATF4, HIF1 and NRF2. Cancer cells largely exploit these factors to thrive and resist therapies. In this review, we report and discuss the potential therapeutic benefit of disrupting the major Myc/Hypoxia-induced metabolic pathway, also known as fermentative glycolysis or "Warburg effect", in aggressive cancer cell lines. With three examples of genetic disruption of this pathway: glucose-6-phosphate isomerase (GPI), lactate dehydrogenases (LDHA and B) and lactic acid transporters (MCT1, MCT4), we illuminate how cancer cells exploit metabolic plasticity to survive the metabolic and energetic blockade or arrest their growth. In this context of NRF2 contribution to OXPHOS re-activation we will show and discuss how, by disruption of the cystine transporter xCT (SLC7A11), we can exploit the acute lethal phospholipid peroxidation pathway to induce cancer cell death by 'ferroptosis'.