Cadmium and cellular signaling cascades: to be or not to be?

Toxicol Appl Pharmacol. 2009 Aug 1;238(3):221-39. doi: 10.1016/j.taap.2009.01.013. Epub 2009 Jan 29.


The cellular effects of the toxic metal cadmium (Cd) are manifold. A large proportion of the cellular reactions affected by ionic Cd(2+) are mediated by cellular signaling cascades. The aim of this review is to provide a principal understanding of the known physiological signaling cascades, which are recruited by Cd(2+), and to highlight the fact that Cd(2+), similarly to other toxic metals, disrupts physiological signal transduction. In principle, second messengers are generated at the time of receptor activation, are short-lived, and act specifically in space and time through non-covalent binding on effectors to transiently alter their activity. Signaling dysregulation induced by Cd(2+) is reflected by a permanent disruption of transducing modules, resulting in low and/or elevated and constant levels of second messengers, which overwhelm the control mechanisms of signaling. This disturbs physiological cellular functions, gene transcription and regulation and may result in cell death and/or stress-induced adaptation and survival as well as carcinogenesis. The impact of Cd(2+) on Ca(2+)-, cAMP-, NO-, ROS-, MAP-kinase-, PKB/Akt-, nuclear factor-kappa B-, and developmental signaling is critically discussed. The hierarchical as well as cooperative and integrative character of signaling cascades activated by Cd(2+) is illustrated in the kidney proximal tubule, a major target of Cd(2+) toxicity. This review also aspires to pinpoint new avenues of research that may contribute to a more differentiated view of the complex mechanisms underlying Cd(2+) toxicity in target tissues and eventually lead to rationales and strategies for prevention and therapy of Cd(2+) toxicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cadmium / toxicity*
  • Calcium Signaling / drug effects
  • Cyclic AMP / metabolism
  • Environmental Pollutants / toxicity*
  • Hedgehog Proteins / metabolism
  • Humans
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism


  • Environmental Pollutants
  • Hedgehog Proteins
  • NF-kappa B
  • Reactive Oxygen Species
  • Wnt Proteins
  • beta Catenin
  • Cadmium
  • Nitric Oxide
  • Cyclic AMP
  • Mitogen-Activated Protein Kinases