Metabolic adaptation of tumor cells under chronic acidosis: a shift towards reductive glutamine metabolism driven by the SIRT1/HIF2 axis

Cancer progression is strongly influenced by the physico-chemical properties of the tumor microenvironment. In particular, tumor cells must adapt to survive under low pO2 and low pH. Although the impact of hypoxia on tumor metabolism is well described, little is known on how tumor cells adapt their metabolism to acidosis. Here, we exposed tumor cells derived from various tissues to low pH conditions (pH 6.5) for several weeks until they ended up proliferating at the same rate as parent cells maintained at pH 7.4. This low pH acclimation triggered the reprogramming of tumor cells from a mainly glycolytic metabolism towards the preferred use of glutamine as documented by tracking the fate of [U-13C] glucose and [U-13C] glutamine by GC-MS analysis of metabolites. The metabolic switch was mediated by SIRT1, a protein deacetylase activated by the increased pool of NAD+ in low pH-adapted cells, through two distinct mechanisms. First, free acetate acted as a counteranion to export excess protons out of the cells via MCT1, maintaining the intracellular pH in a physiological range. Second, SIRT1 stimulated the activity of HIF2 thereby supporting the glutamine metabolism via the upregulation of the glutamine transporter SLC1A5 and enzymes supporting the reductive glutamine metabolism including IDH1. Finally, pharmacological inhibition of either glutamine metabolism with the glutaminase inhibitor BPTES or SIRT1 deacetylase activity preferentially killed low pH-adapted cancer cells in vitro (vs. parent cells) and delayed the growth of corresponding tumor xenografts in vivo. Altogether, these data indicate that a major metabolic shift from glucose to glutamine metabolism is induced in tumor cells chronically exposed to an acidic environment and importantly makes them particularly suited for dedicated pharmacological treatments