Leukemia cells are highly dependent on
glucose and
glutamine as bioenergetic and biosynthetic fuels. Inhibition of the metabolism of
glucose but also of
glutamine is thus proposed as a therapeutic modality to block
leukemia cell growth. Since
glucose also supports protein glycosylation, we wondered whether part of the growth inhibitory effects resulting from glycolysis inhibition could indirectly result from a defect in glycosylation of
glutamine transporters. We found that ASCT2/SLC1A5, a major
glutamine transporter, was indeed deglycosylated upon
glucose deprivation and
2-deoxyglucose exposure in HL-60 and K-562
leukemia cells. Inhibition of glycosylation by these modalities as well as by the bona fide glycosylation inhibitor
tunicamycin however marginally influenced
glutamine transport and did not impact on ASCT2 subcellular location. This work eventually unraveled the dispensability of ASCT2 to support HL-60 and K-562
leukemia cell growth and identified the upregulation of the neutral
amino acid antiporter LAT1/
SLC7A5 as a mechanism counteracting the inhibition of glycosylation. Pharmacological inhibition of LAT1 increased the growth inhibitory effects and the inactivation of the mTOR pathway resulting from glycosylation defects, an effect further emphasized during the regrowth period post-treatment with
tunicamycin. In conclusion, this study points towards the underestimated impact of glycosylation inhibition in the interpretation of metabolic alterations resulting from glycolysis inhibition, and identifies LAT1 as a therapeutic target to prevent compensatory mechanisms induced by alterations in the glycosylating process.