Enhanced glycolysis, regulated by HIF-1α via MCT-4, promotes inflammation in arsenite-induced carcinogenesis.

Abstract

Arsenite is well established as a human carcinogen, but the molecular mechanisms leading to arsenite-induced carcinogenesis are complex and elusive. Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite is unknown. We have found that, with chronic exposure to arsenite, L-02 cells undergo a metabolic shift to glycolysis. In liver cells exposed to arsenite, hypoxia inducible factor-1α (HIF-1α) and monocarboxylate transporter-4 (MCT-4) are over-expressed. MCT-4, directly mediated by HIF-1α, maintains a high level of glycolysis, and the enhanced glycolysis promotes pro-inflammatory properties, which are involved in arsenite carcinogenesis. In addition, serum lactate and cytokines are higher in arsenite-exposed human populations, and there is a positive correlation between them. Moreover, there is a positive relationship between lactate and cytokines with arsenic in hair. In sum, these findings indicate that MCT-4, mediated by HIF-1α, enhances the glycolysis induced by arsenite. Lactate, the end product of glycolysis, is released into the extracellular environment. The acidic microenvironment promotes production of pro-inflammatory cytokines, which contribute to arsenite-induced liver carcinogenesis. These results provide a link between the induction of glycolysis and inflammation in liver cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.

• Authors: Fei Luo, Zhonglan Zou, Xinlu Liu, Min Ling, Qingling Wang, Qi Wang, Lu Lu, Le Shi, Yonglian Liu, Qizhan Liu, Aihua Zhang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 38 Issue 6 Pg. 615-626 (06 01 2017) ISSN: 1460-2180 [Electronic] England
• PMID: 28419250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Arsenites
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Monocarboxylic Acid Transporters
• Muscle Proteins
• SLC16A4 protein, human
• Teratogens
• arsenite

Topics

• Animals
• Arsenites (toxicity)
• Cell Transformation, Neoplastic (chemically induced, metabolism)
• Glycolysis (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Inflammation (chemically induced, metabolism, pathology)
• Liver Neoplasms (chemically induced, metabolism, pathology)
• Monocarboxylic Acid Transporters (metabolism)
• Muscle Proteins (metabolism)
• Teratogens (toxicity)
• Tumor Cells, Cultured