Redox Modification of Hypoxia Inducible Factor 1a under Hypoxia

초록

Hypoxia inducible factor 1alpha (HIF-1 ) plays a major role in the mammalian response to oxygen deficiency. It was found that hypoxia is a common character in many types of solid tumors. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. Therefore targeting HIF-1 is an attractive strategy, with the potential for disrupting multiple pathways crucial for tumor growth. In the present work, we demonstrate that de-glutathionylating enzyme inhibitor treatment induces HIF-1 protein levels. This effect was completely reversed by glutathione depletion with L-Buthionine sulfoximine treatment, indicating that S-glutathionylation, formation of protein-mixed disulfides was related to HIF-1 protein stability. Moreover, cells expressing de-glutathionylating enzyme were resistant in inducing HIF-1 under hypoxic condition. The data presented herein confirmed the occurrence of a redox-dependent regulation of HIF-1 and may have important implications for development of new drugs