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Title

Differential cytostatic and apoptotic effects of ecteinascidin-743 in cancer cells: Transcription-dependent cell cycle arrest and transcription-independent JNK and mitochondrial mediated apoptosis

AuthorsGajate, Consuelo; An, Feiyun; Mollinedo, Faustino
Issue Date1-Nov-2002
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 277(44): 41580-41589 (2002)
AbstractWe have found that ecteinascidin-743 (ET-743) inhibited cell proliferation at 1-10 ng/ml, leading to S and G2/M arrest and subsequent apoptosis, and induced early apoptosis without previous cell cycle arrest at 10100 ng/ml in cancer cells. ET-743-mediated apoptosis, did not involve Fas/CD95. ET-743 induced c-Jun NH2terminal kinase (JNK) and caspase-3 activation, and JNK and caspase inhibition prevented ET-743-induced apoptosis. ET-743 failed to promote apoptosis in caspase-3-deficient MCF-7 cells, further implicating caspase-3 in its proapoptotic action. Overexpression of bcl-2 by gene transfer abrogated ET-743-induced apoptosis, but cells underwent cell cycle arrest. ET-743 triggered cytochrome c release from mitochondria that was inhibited by Bcl-2 overexpression. Inhibition of transcription or protein synthesis did not prevent ET-743induced apoptosis, but abrogated ET-743-induced cell cycle arrest. Microarray analyses revealed changes in the expression of a small number of cell cycle-related genes (p21, GADD45A, cyclin G2, MCM5, and histones) that suggested their putative involvement in ET-743-induced cell cycle arrest. These data indicate that ET-743 is a very potent anticancer drug showing dose-dependent cytostatic and proapoptotic effects through activation of two different signaling pathways, namely a transcriptiondependent pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis that involves mitochondria, JNK, and caspase-3.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M204644200
URIhttp://hdl.handle.net/10261/60110
DOI10.1074/jbc.M204644200
Identifiersissn: 0021-9258
e-issn: 1083-351X
Appears in Collections:(IBMCC) Artículos
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