Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells

Abstract

HIF-1 activation has been well known as an adaptive strategy to hypoxia. Recently it became clear that hypoxia was often accompanied by insufficient supply of glucose or amino acids as a common result of poor circulation that frequently occurs in solid tumors and ischemic lesions, creating a mixed nutrient insufficiency. In response to nutrient insufficiency, stressed cells elicit survival strategies including activation of AMPK and HIF-1 to cope with the stress. Particularly, in solid tumors, HIF-1 promotes cell survival and migration, stimulates angiogenesis, and induces resistance to radiation and chemotherapy. Interestingly, radiation and some chemotherapeutics are reported to trigger the activation of AMPK. Here we discuss the recent advances that may potentially link the stress responsive mechanisms including AMPK activation, ATF4 activation and the enhancement of Hsp70/Hsp90 function to HIF-1 activation. Potential implication and application of the stress-facilitated HIF-1 activation in solid tumors and ischemic disorders will be discussed. A better understanding of HIF-1 activation in cells exposed to stresses is expected to facilitate the design of therapeutic approaches that specifically modulate cell survival strategy.

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

“…Due to inefficient blood flow through the newly formed immature blood vessels within solid tumours, including HCC, tumour cores usually experience hypoxic conditions, which induces HIF-1α, a trancription factor known to promote chemotherapy resistance by several different mechanism4243. Hyperthermia also increases the blood flow in solid tumours6 and thereby may increase delivery of 17-DMAG to the poorly vascularized tumour cores.…”

Cellular stress response mechanisms as therapeutic targets of ginsenosides

“…Moreover, HIF‐1 is a heterodimer composed of an oxygen‐sensitive subunit, HIF‐1α, and a constitutively‐expressed subunit, HIF‐1β. Under normal conditions, HIF‐1α is degraded by posttranslational modifications, such as the ubiquitin–proteasome pathway; however, under hypoxic conditions, activated HIF‐1α becomes stable, enters the nucleus, binds to HIF‐1β, and then recruits coactivator p300/CBP to regulate the expression of target genes, facilitating cell survival under hypoxic conditions . Moreover, HIF‐1α regulates a series of genes that play key roles in angiogenesis, iron and glucose metabolism, as well as cell proliferation and survival.…”

“…HIF‐1α activation has been well characterized as a cellular adaptive response to hypoxia. Recently, it has been demonstrated that hypoxia is often involved under conditions of an insufficient nutrition supply commonly caused by the poor circulation due to ischemic lesions and solid tumors . Nutrient insufficiency, particularly hypoxia, substantially contributes to the initiation and progression of ischemic disorders.…”

Monocyte Chemoattractant Protein‐Induced Protein 1 Targets Hypoxia‐Inducible Factor 1α to Protect Against Hepatic Ischemia/Reperfusion Injury

“…5C). Accordingly, the mRNA expression of HIF-1α target genes, including Hmox-1 (heme oxygenase 1), Glut-1 (glucose transporter 1), and Vegf (vascular endothelial growth factor) (13,14,21) were significantly upregulated, whereas Hif-1α itself was not altered by MCPIP1 overexpression (Fig. 5D).…”

“…One of them, hypoxia-inducible factor 1α (HIF-1α), is a transcription factor regulating diverse biological processes such as tumorigenesis, metabolism, and angiogenesis. (13,14) Physiologically, HIF-1α is proline-hydroxylated by prolyl hydroxylase domain (PHD) enzymes and subsequently ubiquitinated by von Hippel-Lindau for degradation through the ubiquitin-proteasome pathway. (14)(15)(16) HIF-1α activation has been documented in multiple pathological conditions through different mechanisms.…”