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Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

L. Plecitá-Hlavatá, J. Ježek, P. Ježek,

. 2015 ; 47 (6) : 467-76. [pub] 20151008

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc16028122
E-zdroje Online Plný text

NLK ProQuest Central od 1997-02-01 do Před 1 rokem
Medline Complete (EBSCOhost) od 2011-02-01 do Před 1 rokem
Health & Medicine (ProQuest) od 1997-02-01 do Před 1 rokem

Cancer cell bioenergetics, maintaining mixed aerobic glycolysis (Warburg phenotype) and oxidative phosphorylation (OXPHOS), is not fully elucidated. Hypoxia-dependent OXPHOS suppression determines aerobic glycolysis. To elucidate further details, we studied hypoxic adaptation (up to 72 h at 5 % oxygen) of hepatocellular carcinoma HepG2 cells. The key regulatory component, hypoxia-inducible factor (HIF)-1α (HIF-1α) was stabilized at 5 h in 5 % oxygen for all three studied regimens, i.e. in glycolytic cells at 5 mM or 25 mM glucose, or in aglycemic (OXPHOS) cells when glucose was replaced by galactose. However, the conventional HIF-mediated suppression of respiration was prevented at aglycemia, which correlated with a high proportion of unphosphorylated pyruvate dehydrogenase (PDH) at 5 % oxygen. Such a modified HIF response in OXPHOS cells, termed as a non-canonical one, contrasted to conventional respiration suppression down to 45 % or 43 %, observed in hypoxia-adapted glycolytic cells at 5 mM or 25 mM glucose, respectively. These hypoxic glycolytic cells had normally highly phosphorylated PDH and most likely utilized pyruvate by aminotransferase reaction of glutaminolysis to feed at least suppressed respiration. Also, glycolytic cells were rather resistant towards the staurosporine-induced apoptosis, whereas aglycemic (OXPHOS) HepG2 cells exhibited much higher susceptibility. We conclude that aglycemia modulates the hypoxic HIF signaling toward a non-canonical response that is unable to carry out complete PDH phosphorylation, allowing a high pyruvate input for OXPHOS from the elevated glycolysis, which together with ongoing glutaminolysis maintain a virtually unchanged respiration. Similar OXPHOS revival may explain distinct tumor sensitivity to chemotherapy and other pharmacological interventions.

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