Nickel is a ubiquitous environmental transition metal that is widely used in industry. Epidemiological studies indicate that chronic occupational exposure to nickel (Ni) compounds induces human lung and nasal cancers [1]. So far,however, little is known about molecular mechanisms of nickel-induced malignant transformation and tumor development. This study shows that the Nrf2 (nuclear factor erythroid 2-related factor 2) is highly expressed in both human lung tumor tissue and in nickel-transformed human lung bronchial epithelial BEAS-2B cells. Basal ROS(reactive oxygen species) levels are extremely low in nickel-transformed BEAS-2B cells and this correlates with elevated expressions of both antioxidant enzymes and anti-apoptotic proteins. Low levels of ROS and expression levels of antioxidant enzymes and anti-apoptotic proteins are tightly regulated by Nrf2. Autophagy inhibition,induced by pharmacologically or genetically, enhanced nickel-induced apoptosis, indicating that the induction of autophagy is the cause of apoptosis resistance in nickel-transformed cells. This study also shows that in nickel-transformed cells, inhibition of apoptosis cause decreases autophagy in nickel-transformed cells. Additionally, Stat3,which is up-regulated by Nrf2, controls autophagy induction in nickel-transformed cells. Collectively, this study demonstrates that constitutive high Nrf2 expression parallel inhibits apoptosis by an up-regulation of antioxidant enzymes and anti-apoptotic proteins, and increases autophagy via Stat3 signalling
