Regulation of Cellular Sensitivity to Oxidative Stress by HIF‐1alpha Signaling Pathway and Glutathione Level

The aim of this study was to identify the intracellular molecule(s) that sensitively responds to intracellular redox state and thus potentially act as redox sensor. As an initial step toward finding intracellular redox sensor(s) governing cellular signaling for oxidative stress and/or redox state we measured the levels of some proteins previously reported as redox sensors (PHD2, HIF‐1alpha, MAPK) after treatment with hydrogen peroxide in the absence and presence of antioxidants or antioxidant enzyme inducers including delphinidin, phenylisothiocyanate, benzyl‐isothiocyanate, and sulforaphane. We also tested whether HIF‐alpha signaling and glutathione is involved in augmenting or dampening oxidative stress‐induced signaling by measuring the expression of the same battery of proteins in the absence and presence of buthionine sulfoximine, an inhibitor of de novo synthesis of glutathione, or in cells lacking HIF‐1 signaling pathway. That is, we hypothesized that glutathione and HIF‐1 signaling pathway act as a buffer for oxidative stress or reduced status in the cell, and their depletion will bring out increased sensitivity for oxidative stress, showing the increased expression of antioxidant enzymes upon exposure to oxidative stress or some phytochemicals. Overall, our current data were found to support the hypothesis.