LACTB-mediated tumour suppression by increased mitochondrial lipid metabolism

Metabolism has long been known to be a driver of cancer. In the 1920s, Otto Warburg formulated the hypothesis that virtually all cancer cells become addicted to glucose and glucose metabolism with the production of large amounts of lactate, even in conditions of oxygen availability. This metabolic reprogramming, coined as ‘Warburg effect’or ‘aerobic glycolysis’, indeed favours cell transformation and tumour growth.¹ Yet aerobic glycolysis does not explain many of the metabolic changes that occur in cancer, nor it is just a passive adaptation to damaged mitochondria, which in fact are often intact and functional in cancers.² We are only starting to understand the biochemical and molecular basis of the metabolic requirements of cancers, but altered metabolism is now viewed as a hallmark of cancer.^{2, 3}

Much focus has been devoted to oncogenic mechanisms. Classical oncogenes are capable of driving anabolic growth via direct control of metabolic genes. Examples are KRAS leading to the upregulation of the glucose transporter GLUT1, or Myc causing increased expression of LDHA and GLS, involved in lactate generation and mitochondrial glutamine metabolism, respectively. Some metabolic enzymes have been shown to act directly as oncogenes such as PKM2 and PFKFB3 via means of alternative splicing mechanisms as well as hexokinase II, fatty acid synthase and others via increased copy number. Last but not the least, a number of metabolites present oncogenic features, such as 2HG, fumarate, succinate and lactate.^{2, 4}

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