Abstract
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.
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Acknowledgments
We apologize to the many scientists whose work we were not able to credit due to space restrictions. We thank the current and previous members of the laboratory for many stimulating ideas, and Ann Cuypers, Andrea Hartwig, Wolfgang Maret and Jean-Marc Moulis for helpful discussions. Research in the laboratory is funded by The German Research Foundation (DFG) (grants FT345/8-1 to FT345/11-1), the Westermann-Westerdorp Foundation and the Centre for Biomedical Research and Training (ZBAF) at the University of Witten/Herdecke.
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Thévenod, F., Lee, WK. Cadmium and cellular signaling cascades: interactions between cell death and survival pathways. Arch Toxicol 87, 1743–1786 (2013). https://doi.org/10.1007/s00204-013-1110-9
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DOI: https://doi.org/10.1007/s00204-013-1110-9