HIF-1 Signaling Pathway

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator induced by hypoxia, and a modulator of oxygen homeostasis and physiological responses ⁽¹⁾. In hypoxic conditions, HIF-1 plays an essential role in the adaptation of cells and organs to changes related to the presence of oxygen ⁽⁵⁾, and it is required to maintain the pluripotency and survival of stem cells under hypoxic conditions ⁽⁶⁾.

Hypoxia inducible factor-1 α (HIF-1α) is the key responder adapted to tumor hypoxia. Under hypoxia conditions, HIF-1α signaling is activated and responsible for cell biology associated with metabolism, inflammation, vascular homeostasis and tumorigenesis ⁽³⁾. HIF-1 regulates tumor biological behavior by influencing apoptotic/proliferative activity, vasomotor function, energy metabolism, and angiogenesis ⁽⁴⁾.
Previous research indicates that hypoxia increases the population of lung cancer stem cells resistant to gefitinib in EGFR mutation-positive NSCLC, and the HIF-1 signaling pathway is activated in EGFR-TKI-resistant lung cancer cells ⁽²⁾.
HIF-1α activation is related to the development of multidrug resistance and hypoxia-induced EMT in tumor cells ⁽⁴⁾. Moreover, recent findings suggest that HIF-1α-activated autophagy is a crucial factor in the promotion of cell survival under the distressed microenvironment, thereby leading to the chemo-/radioresistance ⁽⁷⁾.