4.6 Article

Activation of multiple proteolysis systems contributes to acute cadmium cytotoxicity

Journal

MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 477, Issue 3, Pages 927-937

Publisher

SPRINGER
DOI: 10.1007/s11010-021-04298-9

Keywords

Cadmium acute toxicity; Proteolysis; Cytotoxicity; Topoisomerase; Metals

Categories

Funding

  1. Ministry of Science and Technology [MOST 107-2911-I-002-531, 109-2320-B-002-031]
  2. Center of Precision Medicine from the Featured Area Research Center Program
  3. MOST in Taiwan [NTU 110L901401, MOST 110-2634-F-002-004]

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Cadmium exposure activates multiple proteolytic systems and ROS formation, leading to intracellular damage and cytotoxicity.
Cadmium exhibits both toxic and carcinogenic effects, and its cytotoxicity is linked to various cellular pathways, such as oxidative stress, ubiquitin-proteasome, and p53-mediated response pathways. The molecular mechanism(s) underlying cadmium cytotoxicity appears to be complex, but remains largely unclear. Here, we examined the effects of cadmium on the protein catabolism using two surrogate markers, DNA topoisomerases I and II alpha and its contribution to cytotoxicity. We have found that cadmium exposure induced time- and concentration-dependent decreases in the protein level of surrogate markers and therefore suggest that cadmium may be involved in proteolysis system activation. A pharmacological study further revealed the novel role(s) of these proteolytic activities and reactive oxygen species (ROS) in the cadmium-induced acute toxicity: (i) Proteasome inhibition only partially relieved the cadmium-induced proteolysis of topoisomerases; (ii) Moreover, we report for the first time that the activation of metalloproteases, serine proteases, and cysteine proteases contributes to the acute cadmium cytotoxicity; (iii) Consistent with the notion that both ROS generation and proteolysis system activation contribute to the cadmium-induced proteolysis and cytotoxicity, the scavenger N-acetylcysteine and aforementioned protease inhibition not only reduced the cadmium-induced topoisomerase degradation but also alleviated the cadmium-induced cell killing. Taken together, acute cadmium exposure may activate multiple proteolytic systems and ROS formation, subsequently leading to intracellular damage and cytotoxicity. Thus, our results provide a novel insight into potential action mechanism(s) by which cadmium exerts its cytotoxic effect and suggest potential strategies to prevent cadmium-associated acute toxicity.

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