HIF-1α Metabolic Pathways in Human Cancer

Oxygen is directly involved in many key pathophysiological processes. Oxygen deficiency, also known as hypoxia, could have adverse effects on mammalian cells, with ischemia in vital tissues being the most significant (Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol 164(6): 1875-1882, 2004); therefore, timely adaptive responses to variations in oxygen availability are essential for cellular homeostasis and survival. The most critical molecular event in hypoxic response is the activation and stabilization of a transcriptional factor termed hypoxia-induced factor-1 (HIF-1) that is responsible for the upregulation of many downstream effector genes, collectively known as hypoxia-responsive genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes; thus, HIF-1-mediated pathways are equally pivotal in both physiology and pathology.As we gain knowledge on the molecular mechanisms underlying the regulation of HIF-1, a great focus has been placed on elucidating the cellular function of HIF-1, particularly the role of HIF-1 in cancer pathogenesis pathways such as proliferation, invasion, angiogenesis, and metastasis. In cancer, HIF-1 is directly involved in the shift of cancer tissues from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. Although targeting HIF-1 as a cancer therapy seems like an extremely rational approach, owing to the complex network of its downstream effector genes, the development of specific HIF-1 inhibitors with fewer side effects and more specificity has not been achieved. Therefore, in this review, we provide a brief background about the function of HIF proteins in hypoxia response with a special emphasis on the unique role played by HIF-1α in cancer growth and invasiveness, in the hypoxia response context.