Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway and its Potential for Therapeutic Intervention in Malignancy and Ischemia

By J. Ziello, Ion S. Jovin, Yan Huang. The Yale Journal of Biology and Medicine, 2007

663 citations recorded by the source corpus.

Hypoxia-Inducible Factor (HIF)-1 is a dimeric protein complex that plays an integral role in the body's response to low oxygen concentrations, or hypoxia. HIF-1 is among the primary genes involved in the homeostatic process, which can increase vascularization in hypoxic areas such as localized ischemia and tumors. It is a transcription factor for dozens of target genes; HIF-1 is also essential for immunological responses and is a crucial physiological regulator of homeostasis, vascularization, and anaerobic metabolism. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. In contrast, as HIF-1 allows for survival and proliferation of cancerous cells due to its angiogenic properties, inhibition potentially could prevent the spread of cancer. With a growing understanding of the HIF-1 pathway, the inhibition and stimulation of its transcriptional activity via small molecules is now an attractive goal. Gene therapy to achieve both vessel proliferation and tumor regression has been demonstrated in animal studies but requires significant improvement and modification before becoming commercially available. This review focuses on the potential of the HIF-1 pathway in therapeutic intervention for the treatment of diseases such as cancer and ischemia.

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1. I. Klaassen
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4. Hang Zhang
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6. Xiaoyi Pang
7. C. Roma-Rodrigues
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Citations in the corpus

• Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. (2013, background): “HIF-1 is a crucial player in the regulation of cellular oxidative metabolism and mediates many adaptive endogenous mechanisms during hypoxia by transcriptional activation of specific target genes that function to restore oxygen supply and/or improve survival of cells in a hypoxic environment (Semenz”
• Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions (2022, background): “Also, HIF-1α expression strongly correlates with ROS levels, with HIF-1α chains stabilized by the large quantities of ROS generated under hypoxia.(28,107) In a positive feedback loop, lack of oxygen and glucose due to ischemia may enhance HIF-1 expression, thereby causing oxidative stress and furthe”
• Targeting Tumor Microenvironment for Cancer Therapy (2019, background): “This metabolic shift is mediated by the HIF-1 transcriptional regulators that, under hypoxia conditions, induce glucose transporters (GLUTs) to increase glucose import, and regulate the metabolism, favoring anaerobic glycolysis over oxidative phosphorylation [11,19,21].”
• The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress (2016, background): “HIF-1 transcription factor plays an important role in the response of tumor cells to hypoxic conditions and is essential for regulating the expression of genes involved in homeostatic processes [50].”