BxPC-3 cells: growth in different nutrients

The MondoA transcription factor forms a heterocomplex with its obligate partner Mlx to regulate ~75% of glucose-dependent transcription. By mediating glucose-induced activation of thioredoxin-interacting protein (TXNIP), MondoA directly represses glucose uptake. Given the predominant role of MondoA in controlling glucose-dependent transcription and glucose uptake, we asked whether glutamine regulates MondoA activity. Expression profiles from glucose and glutamine starved BxPC-3 cells (-G-Q) were compared with those from cells grown in glucose only (+G-Q), glutamine only (-G+Q) or glucose plus glutamine (+G+Q). As expected, TXNIP expression was highly induced by glucose. However, the addition of glutamine repressed the glucose-dependent induction of TXNIP. We show that glutamine inhibits MondoA-dependent transcriptional activation of TXNIP by triggering the recruitment of a histone deacetylase-dependent corepressor to the amino terminus of MondoA. Consistent with the repression of TXNIP, glucose uptake is elevated in cells grown in the presence of glucose and glutamine. Finally, alpha-ketoglutarate, a tricarboxylic acid cycle intermediate, also blocks MondoA-dependent activation of TXNIP and stimulates glucose uptake. Together, these results suggest that glutamine-dependent mitochondrial anapleurosis stimulates glucose uptake by restricting TXNIP expression via MondoA:Mlx complexes. Four growth conditons; four biological replicates