Protein S-glutathionylation induced by hypoxia increases hypoxia-inducible factor-1α in human colon cancer cells

초록

Hypoxia is a common characteristic of many types of solid tumors. Intratumoral hypoxia selects for tumor cells that survive in a low oxygen environment, undergo epithelial-mesenchymal transition, are more motile and invasive, and show gene expression changes driven by hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation. Therefore, targeting HIF-1 alpha is an attractive strategy for disrupting multiple pathways crucial for tumor growth. In the present study, we demonstrated that hypoxia increases the S-glutathionylation of HIF-1 alpha and its protein levels in colon cancer cells. This effect is significantly prevented by decreasing oxidized glutathione as well as glutathione depletion, indicating that S-glutathionylation and the formation of protein-glutathione mixed disulfides is related to HIF-1 alpha protein levels. Moreover, colon cancer cells expressing glutaredoxin 1 are resistant to inducing HIF-1 alpha and expressing hypoxia-responsive genes under hypoxic conditions. Therefore, S-glutathionylation of HIF-1 alpha induced by tumor hypoxia may be a novel therapeutic target for the development of new drugs. (C) 2017 Elsevier Inc. All rights reserved.

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