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

• Published in: Marine Drugs Vol. 13; no. 10; pp. 6505 - 6520
• Main Authors: Kleppe, Rune, Herfindal, Lars, Døskeland, Stein Ove
• Format: Journal Article Book Review
• Language: English
• Published: Switzerland MDPI AG 22.10.2015; MDPI
• Subjects: Animals; apoptosis; Apoptosis - drug effects; Carcinogens - pharmacology; Cell death; Cell Death - drug effects; Enzyme Inhibitors - pharmacology; Humans; inhibitor; microcystin; Microcystins - pharmacology; nodularin; okadaic acid; Okadaic Acid - pharmacology; Oxazoles - pharmacology; Peptides, Cyclic - pharmacology; Phosphoprotein Phosphatases - antagonists & inhibitors; protein phosphatase; Reactive Oxygen Species - metabolism; Review; nodularin; cell death; inhibitor; apoptosis; okadaic acid; protein phosphatase; microcystin
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md13106505

Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca(2+)/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity.