Cadmium and cellular signaling cascades: interactions between cell death and survival pathways

Cellular stress elicited by the toxic metal Cd2+ does not coerce the cell into committing to die from the onset. Rather, detoxification and adaptive processes are triggered concurrently, allowing survival until normal function is restored. With high Cd2+, death pathways predominate. However, if sublethal stress levels affect cells for prolonged periods, as in chronic low Cd2+ exposure, adaptive and survival mechanisms may deregulate, such that tumorigenesis ensues. Hence, death and malignancy are the two ends of a continuum of cellular responses to Cd2+, determined by magnitude and duration of Cd2+ stress. Signaling cascades are the key factors affecting cellular reactions to Cd2+. This review critically surveys recent literature to outline major features of death and survival signaling pathways as well as their activation, interactions and cross talk in cells exposed to Cd2+. Under physiological conditions, receptor activation generates 2nd messengers, which are short-lived and act specifically on effectors through their spatial and temporal dynamics to transiently alter effector activity. Cd2+ recruits physiological 2nd messenger systems, in particular Ca2+ and reactive oxygen species (ROS), which control key Ca2+- and redox-sensitive molecular switches dictating cell function and fate. Severe ROS/Ca2+ signals activate cell death effectors (ceramides, ASK1-JNK/p38, calpains, caspases) and/or cause irreversible damage to vital organelles, such as mitochondria and endoplasmic reticulum (ER), whereas low localized ROS/Ca2+ levels act as 2nd messengers promoting cellular adaptation and survival through signal transduction (ERK1/2, PI3K/Akt-PKB) and transcriptional regulators (Ref1-Nrf2, NF-κB, Wnt, AP-1, bestrophin-3). Other cellular proteins and processes targeted by ROS/Ca2+ (metallothioneins, Bcl-2 proteins, ubiquitin–proteasome system, ER stress-associated unfolded protein response, autophagy, cell cycle) can evoke death or survival. Hence, temporary or permanent disruptions of ROS/Ca2+ induced by Cd2+ play a crucial role in eliciting, modulating and linking downstream cell death and adaptive and survival signaling cascades.