Hypoxia/pseudohypoxia‐mediated activation of hypoxia‐inducible factor‐1α in cancer

• Published in: Cancer science Vol. 110; no. 5; pp. 1510 - 1517
• Main Authors: Hayashi, Yoshihiro, Yokota, Asumi, Harada, Hironori, Huang, Gang
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2019; John Wiley and Sons Inc
• Subjects: Biosynthesis; Cancer; Carcinoma; Cell adhesion & migration; Cell Hypoxia; Enzymes; Gene expression; Gene Expression Regulation, Neoplastic; Glucose; Glucose metabolism; Glycolysis; HIF1A; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kinases; Lactic Acid - metabolism; Metabolism; Metastases; Mutation; Neoplasms - genetics; Neoplasms - metabolism; oncometabolite; Phosphorylation; Protein Stability; Proteins; pseudohypoxia; Pyruvic Acid - metabolism; Review; Signal Transduction; Tumors; Warburg effect; Warburg, Otto; pseudohypoxia; hypoxia; oncometabolite; HIF1A; Warburg effect
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.13990

Since the first identification of hypoxic cells in sections of carcinomas in the 1950s, hypoxia has been known as a central hallmark of cancer cells and their microenvironment. Indeed, hypoxia benefits cancer cells in their growth, survival, and metastasis. The historical discovery of hypoxia‐inducible factor‐1α (HIF1A) in the early 1990s had a great influence on the field as many phenomena in hypoxia could be explained by HIF1A. However, not all regions or types of tumors are necessarily hypoxic. Thus, it is difficult to explain whole cancer pathobiology by hypoxia, especially in the early stage of cancer. Upregulation of glucose metabolism in cancer cells has been well known. Oxygen‐independent glycolysis is activated in cancer cells even in the normoxia condition, which is known as the Warburg effect. Accumulating evidence and recent advances in cancer metabolism research suggest that hypoxia‐independent mechanisms for HIF signaling activation is a hallmark for cancer. There are various mechanisms that generate pseudohypoxic conditions, even in normoxia. Given the importance of HIF1A for cancer pathobiology, the pseudohypoxia concept could shed light on the longstanding mystery of the Warburg effect and accelerate better understanding of the diverse phenomena seen in a variety of cancers. Accumulating evidence has revealed that hypoxia‐inducible factor (HIF) signaling can be activated through a variety of hypoxia‐independent mechanisms, even in normoxia. Given the importance of HIFs for glucose metabolism and cancer pathobiology, the pseudohypoxia concept could accelerate better understanding of the diverse phenomena seen in a variety of cancers.