Inhibition of GSK3β by indirubins restores HIF-1α accumulation under prolonged periods of hypoxia/anoxia

Hypoxia inducible factor 1 is regulated by the appearance of the HIF-1α subunit. HIF-1α is subjected to proteasomal destruction or enhanced protein translation, which requires the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. We investigated how PI3K/Akt and glycogen synthase kinase 3β (GSK3β) affect HIF-1α in human RKO cells under prolonged periods of severe hypoxia/anoxia. 16- to 32-h lasting incubations attenuated Akt activity and decreased HIF-1α protein. This was reproduced by blocking PI3K with LY294002. GSK3β inhibition by indirubins circumvented the effect of hypoxia/anoxia or LY294002 on HIF-1α. Ruling stability regulation of HIF-1α protein and/or enhanced transcription of HIF-1α mRNA via GSK3β inhibition out is suggestive for translational modulation of HIF-1α under the influence of GSK3β.