PI3K/Akt and HIF‑1 signaling pathway in hypoxia‑ischemia (Review)

Abstract

Hypoxia-ischemia (H-I) is frequently observed in perinatal asphyxia and other diseases. It can lead to serious cardiac injury, cerebral damage, neurological disability and mortality. Previous studies have demonstrated that the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, which regulates a wide range of cellular functions, is involved in the resistance response to H-I through the activation of proteins associated with survival and inactivation of apoptosis-associated proteins. It can also regulate the expression of hypoxia-induced factor-1α (HIF-1α). HIF-1α can further regulate the expression of downstream proteins involved in glucose metabolism and angiogenesis, such as vascular endothelial growth factor and erythropoietin, to facilitate ischemic adaptation. Notably, HIF-1α may also induce detrimental effects. The effects of HIF-1 on ischemic outcomes may be dependent on the H-I duration, animal age and species. Thus, further investigation of the PI3K/Akt signaling pathway may provide further insights of the potential targets for treating diseases accompanied by H-I.

HSP4 triggers epithelial‐mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT

“…There data demonstrated that HSF4 regulated motility and EMT mainly via activating AKT pathway. The previous studies revealed that HSF4 could promote HIF‐1α transcription, 20 and HIF‐1α play an important role in triggering AKT activation 35 . Consistent with these studies, we found HSF4 was positively correlated with HIF‐1α expression, and more importantly, re‐expression HIF‐1α could rescue HCC cells from the inhibitory effects on AKT activation caused by HSF4 knockdown, whereas silence of HIF‐1α abolished the activation effect of HSF4 overexpression on AKT.…”

Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma

“…Since the balance between Akt and p53 signaling is known to determine cell fate toward apoptosis or survival in hypoxia [25][26][27], we validated our results by p53 activity and Akt phosphorylation evaluation with ELISA assays, on three cell lines with different DLK1 cleavage abilities transfected with the various DLK1 constructs. All cell lines showed increased p53 DNA binding after 24 h of hypoxia, but at a later time point U3082MG and U3084MG cells had a persistent increase in DNA-binding ability only in cells transfected with DLK-C form, with levels back to basal in cells transfected with DLK-A or empty vector.…”

Targeting immunometabolism as an anti-inflammatory strategy

“…Whilst aiming to limit Hif-1α expression may be a prime strategy for anticancer therapies and controlling excessive inflammation, target genes of Hif-1α play a critical role in angiogenesis, cell proliferation/survival and glucose/ iron metabolism presenting therapeutic opportunities in stabilizing Hif-1α when treating anemia associated with chronic kidney disease or hypoxia-ischemia during myocardial infarction, stroke and perinatal asphyxia. [170][171][172][173] Dimethyloxalylglycine (DMOG) is a potent driver of Hif-1α activity and acts through the inhibition of PHD resulting in stabilization of Hif-1α protein expression and expression of Hif-1α target genes such as vascular endothelial growth factor (VEGF) and proglycolytic enzymes. 174 Hif-1α plays a key role in promoting expression of erythropoietin (EPO) thereby stimulating production of hemoglobin and red blood cells.…”