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Title

Aplidin® induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation

AuthorsGonzález-Santiago, L.; Suárez, Yajaira; Muñoz-Alonso, María J. ; Cuadrado, Ana ; Martínez, Teresa; Goya, Luis ; Rojas, José María; Muñoz Terol, Alberto
Issue Date2006
PublisherNature Publishing Group
CitationCell Death and Differentiation 13(11): 1968-1981 (2006)
AbstractAplidin® is an antitumor agent in phase II clinical trials that induces apoptosis through the sustained activation of Jun N-terminal kinase (JNK). We report that Aplidin® alters glutathione homeostasis increasing the ratio of oxidized to reduced forms (GSSG/GSH). Aplidin® generates reactive oxygen species and disrupts the mitochondrial membrane potential. Exogenous GSH inhibits these effects and also JNK activation and cell death. We found two mechanisms by which Aplidin® activates JNK: rapid activation of Rac1 small GTPase and downregulation of MKP-1 phosphatase. Rac1 activation was diminished by GSH and enhanced by L-buthionine (SR)-sulfoximine, which inhibits GSH synthesis. Downregulation of Rac1 by transfection of small interfering RNA (siRNA) duplexes or the use of a specific Rac1 inhibitor decreased Aplidin®-induced JNK activation and cytotoxicity. Our results show that Aplidin® induces apoptosis by increasing the GSSG/GSH ratio, a necessary step for induction of oxidative stress and sustained JNK activation through Rac1 activation and MKP-1 downregulation.
URIhttp://hdl.handle.net/10261/77449
DOI10.1038/sj.cdd.4401898
Identifiersdoi: 10.1038/sj.cdd.4401898
issn: 1350-9047
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