Cell Death Inducing Microbial Protein Phosphatase Inhibitors--Mechanisms of Action.
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.
Department of Biomedicine, University of Bergen, Jonas Lies vei 81, N-5009 Bergen, Norway. rune.kleppe@uib.no.
Rune
R
Kleppe
Department of Biomedicine, University of Bergen, Jonas Lies vei 81, N-5009 Bergen, Norway. lars.herfindal@uib.no.|Department of Clinical Science, University of Bergen, Jonas Lies vei 65, N-5021 Bergen, Norway. lars.herfindal@uib.no.
Lars
L
Herfindal
Department of Biomedicine, University of Bergen, Jonas Lies vei 81, N-5009 Bergen, Norway. stein.doskeland@uib.no.
Stein Ove
SO
Døskeland
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism
D002273:Carcinogens; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D052998:Microcystins; D010080:Oxazoles; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; C063998:nodularin; D019319:Okadaic Acid; C078588:microcystin; C059041:calyculin A; D010749:Phosphoprotein Phosphatases
apoptosis; cell death; inhibitor; microcystin; nodularin; okadaic acid; protein  phosphatase