The flipside of the coin is that tumor suppressors often inhibit metabolic pathways that support growth. We have already discussed the “braking” effect of the tumor suppressors NF1 and PTEN on signals downstream of growth factor receptors and RAS, allowing them to oppose the Warburg effect. Indeed, it may be that many (and perhaps all) tumor suppressors that induce growth arrest suppress the Warburg effect. For example, p53, arguably the most important tumor suppressor, upregulates target genes that collectively inhibit glucose uptake, glycolysis, lipogenesis, and the generation of NADPH (a key cofactor needed for the biosynthesis of macromolecules). Thus, it is increasingly clear that the functions of many oncoproteins and tumor suppressors are inextricably intertwined with cellular metabolism.
Beyond the Warburg effect, there are two other links between metabolism and cancer that are of sufficient importance to merit brief mention, autophagy and an unusual set of oncogenic mutations that lead to the creation of oncometabolites, small molecules that appear to directly contribute to the transformed state.
Autophagy is a state of severe nutrient deficiency in which cells not only arrest their growth, but also cannibalize their own organelles, proteins, and membranes as carbon sources for energy production (Chapter 2). If this adaptation fails, the cells die. Tumor cells often seem to be able to grow under marginal environmental conditions without triggering autophagy, suggesting that the pathways that induce autophagy are deranged. In keeping with this, several genes that promote autophagy are tumor suppressors. Whether autophagy is always bad from the vantage point of the tumor, however, remains a matter of active investigation and debate. For example, under conditions of severe nutrient deprivation, tumor cells may use autophagy to become “dormant,” a state of metabolic hibernation that allows cells to survive hard times for long periods. Such cells are believed to be resistant to therapies that kill actively dividing cells, and could therefore be responsible for therapeutic failures. Thus, autophagy may be a tumor’s friend or foe depending on how the signaling pathways that regulate it are “wired” in a given tumor.
Another surprising group of genetic alterations discovered through tumor genome sequencing studies are mutations in enzymes that participate in the Krebs cycle. Of these, mutations in isocitrate dehydrogenase (IDH) have garnered the most interest, as they have revealed a new mechanism of oncogenesis termed oncometabolism (
Fig. 6.24).
The proposed steps in the oncogenic pathway involving IDH are as follows:
IDH acquires a mutation that leads to a specific amino acid substitution involving residues in the active site of the enzyme. As a result, the mutated protein loses it ability to function as an isocitrate dehydrogenase and instead acquires a new enzymatic activity that catalyzes the production of 2-hydroxglutarate (2-HG).
2-HG in turn acts as an inhibitor of several other enzymes that are members of the TET family, including TET2.
TET2 is one of several factors that regulate DNA methylation, which you will recall is an epigenetic modification that controls normal gene expression and often goes awry in cancer. According to the model, loss of TET2 activity leads to abnormal patterns of DNA methylation.
Abnormal DNA methylation in turn leads to misexpression of currently unknown cancer genes, which drive cellular transformation and oncogenesis.
Thus, according to this scenario, mutated IDH acts as an oncoprotein by producing 2-HG, which is considered a prototypical oncometabolite. Oncogenic IDH mutations
Epigenetic changes (DNA methylation, histone modification)
Fig. 6.24 Proposedactionoftheoncometabolite2-hydroxyglutarate(2-HG)incancercellswithmutatedisocitratedehydrogenase(mIDH).