Nrf2 signaling pathway in trace metal carcinogenesis: A cross-talk between oxidative stress and angiogenesis

A large number of people worldwide are affected by chronic metal exposure, which is known to be associated with different type of malignancies. The mechanisms of metal carcinogenicity are complex in nature, and excessive reactive oxygen species (ROS) generation induced by chronic metal exposure, among the other factors, has been proposed as one of the major mechanisms involved in that process. In tumor cells, ROS buildup may lead to cell death through intrinsic and extrinsic signaling pathways. Furthermore, ROS-mediated redox signaling has a crucial role in angiogenesis, which is recognized as an essential step in tumor progression. There are several redox-modulating pathways and among them, the nuclear factor erythroid2-related factor2 (Nrf2), as a sensor of oxidative or electrophilic stress, has introduced as a master regulator of cellular response against environmental stresses. Activation of Nrf2 signaling induces expression of wide variety of antioxidant and detoxification enzymes genes. Thus, this transcription factor has recently received much attention as a target for cancer chemoprevention. But meanwhile, constitutive Nrf2 activation in cancerous cells may promote cancer progression and resistance to chemotherapy. The current review describes the major underlying mechanisms involved in carcinogenesis of trace metals: copper, silver, and cadmium, with a special focus on the Nrf2 signaling pathway as a crossroad between oxidative stress and angiogenesis.