Redox regulation of hypoxia inducible factor 1a under hypoxic condition

초록

Hypoxia inducible factor 1α (HIF-1α) 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-1α and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. Therefore targeting HIF-1α 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-1α 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-1α protein stability. Moreover, cells expressing de-glutathionylating enzyme were resistant in inducing HIF-1α under hypoxic condition. The data presented herein confirmed the occurrence of a redox- dependent regulation of HIF-1α and may have important implications for development of new drugs.