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Cell Death Inducing Microbial Protein Phosphatase Inhibitors--Mechanisms of Action

Rune Kleppe1, Lars Herfindal2,3, Stein Ove Døskeland4

  • 1Department of Biomedicine, University of Bergen, Jonas Lies vei 81, N-5009 Bergen, Norway. rune.kleppe@uib.no.

Marine Drugs
|October 28, 2015
PubMed

Insights

Okadaic acid and microcystin toxins promote tumors and cell death by targeting protein phosphatases. Inhibiting specific enzymes in the arachidonic acid pathway may reduce toxin-induced liver cell death.

Area of Science:

  • Biochemistry
  • Toxicology
  • Cell Biology

Background:

  • Okadaic acid (OA), microcystin (MC), nodularin, and calyculinA are potent tumor promoters and inducers of apoptotic cell death.
  • These toxins exert their effects by inhibiting major cellular serine/threonine protein phosphatases.
  • Their mechanisms involve the interplay between reactive oxygen species (ROS) production and Ca(2+)/calmodulin kinase II (CaM-KII) activation.

Purpose of the Study:

  • To review the mechanisms of tumor promotion and cell death induction by OA and MC.
  • To investigate the role of ROS-producing enzymes in nodularin/MC-induced hepatocyte death.
  • To identify potential therapeutic targets for mitigating OA and MC toxicity.

Main Methods:

  • Literature review of toxin mechanisms.
  • Experimental use of specific enzyme inhibitors to block ROS production.
  • Assessment of nodularin/MC-induced liver cell death.

Main Results:

  • The study highlights the interdependent roles of ROS and CaM-KII in toxin-induced cell death and tumor promotion.
  • Inhibiting enzymes within the arachidonic acid pathway, including phospholipase A2, 5-lipoxygenase, and cyclooxygenases, significantly reduced nodularin/MC-induced hepatocyte death.
  • These findings suggest these enzymes are crucial for mediating the toxic effects of these cyanotoxins.

Conclusions:

  • The arachidonic acid pathway plays a critical role in mediating nodularin/MC-induced liver cell death.
  • Targeting enzymes like phospholipase A2, 5-lipoxygenase, and cyclooxygenases offers a potential strategy to counteract the toxicity of OA and MC.
  • Understanding these pathways provides new avenues for developing interventions against harmful algal bloom toxins.
Keywords:
apoptosiscell deathinhibitormicrocystinnodularinokadaic acidprotein phosphatase

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