Dysregulated metabolism, an emerging hallmark of cancer, provides tumor cells with sufficient energy to maintain critical cellular processes including proliferation and lipid biosynthesis (Metallo and Van-der Heiden, 2013). Critical metabolic pathways utilized by cancer cells rely predominantly on glucose and glutamine as primary nutrient sources. In contrast to aerobic glycolysis (often referred to as the "Warburg effect") where lactate is produced at the expense of pyruvate oxidation in the tricarboxylic acid (TCA) cycle, many tumor cells metabolize glutamine to either maintain TCA cycle function or to generate acetyl-CoA for lipid biosynthesis through reductive carboxylation. Aside from energy production, TCA cycle intermediates are utilized as substrates for biosynthetic (cataplerotic) reactions and therefore need to be replenished (anaplerosis) in order to coordinate respiration (Metallo and Vander Heiden, 2013). Importantly, through oxaloacetate (OAA) generation, pyruvate interconnects carbohydrate, lipid/fatty acid, and amino acid metabolism, thus providing an attractive target for" metabolic and synthetic lethality screens in cancer cells. Recent studies revealed that the mitochondrial pyruvate carriers (MPC1 and MPC2) form a heterocomplex embedded in the inner mitochondrial membrane (Bricker et al., 2012; Herzig et al., 2012). In this issue of Molecular Cell, Schell and colleagues identified MPC1 loss as a common feature of cancer cells, an observation corroborated by epidemio-logical data demonstrating a correlation between low MPC1 expression and poor survival (Schell et al., 2014) (Figure 1). Re-expression of MPCs in colon cancer cells lacking native MPCs increased pyruvate flux into the mitochondria for oxidation via the TCA cycle, though in adherent cell culture did not have any significant effects on proliferation, viability, apoptosis, or necrosis. However, MPC re-expression under conditions of anchorage-independent growth inhibited the growth of colon cancer cells in vitro and in vivo. Interestingly, the authors observed the anti-proliferative phenotype associated with restoration of MPC function to be most prominent in the stem cell compartment (Schell et al., 2014). Although the effect of MPC expression on sternness is clearly metabolic, further studies to elucidate the mechanism(s) underlying the loss of stem cell markers will potentially identify crucial frailties in cancer cells that can be exploited therapeutically.
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