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M204644200v1
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Papers In Press, published online ahead of print August 26, 2002
J. Biol. Chem, 10.1074/jbc.M204644200
Submitted on May 13, 2002
Revised on July 31, 2002
Accepted on August 26, 2002

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

Consuelo Gajate, Feiyun An, and Faustino Mollinedo

Instituto de Biología Molecular y Celular del Cáncer, Universidad de Salamanca, Salamanca 37007

Corresponding Author: fmollin{at}usal.es

We 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 10-100 ng/ml in cancer cells. ET-743-mediated apoptosis did not involve Fas/CD95. ET-743 induced c-Jun NH2-terminal 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-743-induced 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 transcription-dependent pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis that involves mitochondria, JNK, and caspase-3.


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