By contrast, in actively growing cells only a small fraction of the cellular glucose is shunted through the oxidative phosphorylation pathway, such that on average each molecule of glucose metabolized produces approximately four molecules of ATP. Presumably, this balance (heavily biased toward aerobic fermentation, with a bit of oxidative phosphorylation) hits a metabolic “sweet spot” that is optimal for growth. It follows that growing cells do rely on mitochondrial metabolism. However, a major function of mitochondria in growing cells is not to generate ATP, but rather to carry out reactions that generate metabolic intermediates that can be shunted off and used as precursors in the synthesis of cellular building blocks. For example, lipid biosynthesis requires acetyl-CoA, and acetyl-CoA is largely synthesized in growing cells from intermediates such as citrate that are generated in mitochondria.
So how is this profound reprogramming of metabolism, the Warburg effect, triggered in growing normal and malignant cells? As might be guessed, metabolic reprogramming is produced by signaling cascades downstream of growth factor receptors, the very same pathways that are deregulated by mutations in oncogenes and tumors suppressor genes in cancers. Thus, whereas in rapidly dividing normal cells aerobic glycolysis ceases when the tissue is no longer growing, in cancer cells this reprogramming persists due to the action of oncogenes and the loss of tumor suppressor gene function. Some of the important points of cross-talk between pro–growth signaling factors and cellular metabolism are shown in
Fig. 6.23 and include the following: • Growth factor receptor signaling. In addition to transmitting growth signals to the nucleus, signals from growth factor receptors also influence metabolism by
Fig. 6.23 Metabolismandcellgrowth.QuiescentcellsrelymainlyontheKrebscycleforATPproduction;ifstarved,autophagy(self-eating)isinducedtoprovideasourceoffuel.Whenstimulatedbygrowthfactors,normalcellsmarkedlyupregulateglucoseandglutamineuptake,whichprovidecarbonsourcesforsynthesisofnucleotides,proteins,andlipids.Incancers,oncogenicmutationsinvolvinggrowthfactorsignalingpathwaysandotherkeyfactorssuchasMYCderegulatethesemetabolicpathways,analterationknownastheWarburg effect. Krebs cycle ATP CO2 GROWTHtransporter Lipids RTK LysosomeLipid and amino acid catabolism Autophagy transporter Increased glycolytic intermediates Increased glutamine utilization Lactate RTK Growth factor RTK Glutamine RTK Mitochondrial metabolites PI3K Protein synthesis Lipogenesis Nucleotide, amino acid synthesis Akt MYC http://ebooksmedicine.net upregulating glucose uptake and inhibiting the activity of pyruvate kinase, which catalyzes the last step in the glycolytic pathway, the conversion of phosphoenolpyruvate to pyruvate. This creates a damming effect that leads to the buildup of upstream glycolytic intermediates, which are siphoned off for synthesis of DNA, RNA, and protein.
RAS signaling. Signals downstream of RAS upregulate the activity of glucose transporters and multiple glycolytic enzymes, thus increasing glycolysis; promote shunting of mitochondrial intermediates to pathways leading to lipid biosynthesis; and stimulate factors that are required for protein synthesis.
MYC. As mentioned earlier, pro-growth pathways upregulate expression of the transcription factor MYC, which drives changes in gene expression that support anabolic metabolism and cell growth. Among the MYC-regulated genes are those for several glycolytic enzymes and glutaminase, which is required for mitochondrial utilization of glutamine, a key source of carbon moieties needed for biosynthesis of cellular building blocks.