Oxidation and inactivation of low molecular weight protein tyrosine phosphatase by the anticancer drug Aplidin.
The marine plitidepsin Aplidin derived from the Mediterranean tunicate Aplidium albicans is a strong apoptotic inducer with promising antitumor activity. However, little is known about the mechanism of action of the molecule. In this article, we report that Aplidin is cytotoxic for NIH3T3 cells and that its action is exerted through the production of reactive oxygen species (ROS). Rotenone, but not other selective inhibitors of ROS production, blocks the induction of ROS, suggesting the involvement of the mitochondrial respiratory chain in Aplidin action. The intracellular rise of redox potential caused by Aplidin inactivates several molecular targets. Among these targets, we focused our attention on protein tyrosine phosphatases (PTPs). In agreement with the well-characterized effect of ROS-mediated PTP oxidation, due to the presence of a cysteine residue in their catalytic site, we found that Aplidin induces a strong decrease in PTP activity. In particular, since the expression of low molecular weight-PTP (LMW-PTP) is strongly associated with tumor onset and progression, we investigated the effect of Aplidin on this enzyme. Our data show that LMW-PTP is oxidized and inactivated during Aplidin treatment, thus causing a hyper-phosphorylation of its substrate beta-catenin. These findings demonstrate that, at least in part, the antitumoral activity of Aplidin could be due to the direct inhibition of LMW-PTP and its related oncogenic potential.
Taddei
Maria Letizia
ML
Department of Biochemical Sciences, University of Florence, viale Morgagni 50, 50134 Florence, Italy.
Chiarugi
Paola
P
Cuevas
Carmen
C
Ramponi
Giampietro
G
Raugei
Giovanni
G
D000818:Animals; D047630:Depsipeptides / Q000494:pharmacology*; D018450:Disease Progression; D004579:Electron Transport; D005347:Fibroblasts; D051379:Mice; D008970:Molecular Weight; D010084:Oxidation-Reduction; D010456:Peptides, Cyclic; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species
D047630:Depsipeptides; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; D011505:Protein-Tyrosine Kinases; C098980:plitidepsin