Acetate metabolism in cancer cells

Macromolecule biosynthesis is required to duplicate cell components and support proliferation. Studies examining the nutrients used by cancer cells have focused on the contribution of glucose and glutamine carbon for biosynthesis, but the importance of other metabolic fuels is becoming apparent. Labeling of two-carbon units in newly synthesized lipids has been used to infer the nutrients that contribute to the acetyl-CoA pools in cells. Glucoseand glutamine-derived carbon are known to contribute extensively to de novo lipid biosynthesis, and in this issue Kamphorst et al. find that extracellular acetate can also contribute substantially to this process [1]. In normoxia, glucose and glutamine together account for the majority of lipogenic acetyl-CoA, but this fraction falls substantially in hypoxia [2,3]. In hypoxia, flux from glucose to citrate as a source of acetyl-coA decreases, and cells utilize alternative carbon sources to generate this metabolite. Glutamine can provide some of this carbon through reductive carboxylation of glutaminederived α-ketoglutarate to citrate [2,4], but a substantial amount of acetyl-CoA is labeled by neither glucose nor glutamine tracing. Breakdown of lipids scavenged from the environment is one alternate source of acetyl-CoA, but mammalian serum also contains acetate, and the authors found that exogenous acetate could be incorporated into acetyl-CoA and become available for lipid biosynthesis. Surprisingly, for some cell lines in hypoxia, acetate may be a major contributor to acetyl-CoA. Acetate is transported into cells by members of the monocarboxylate transporter family [5] where acetyl-CoA synthetases (ACSS) catalyze conversion to acetyl-CoA. Mammalian cells express mitochondrial and cytosolic forms of ACSS, and the authors cite emerging data from other groups that this enzyme can be important for growth of some tumors. Kamphorst et al. observe that acetate labels acetyl-CoA in hypoxic cells only, and it is interesting to consider whether this is due to increased acetate uptake or increased ACSS activity in low oxygen.