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Originally published In Press as doi:10.1074/jbc.M208303200 on September 25, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49870-49876, December 20, 2002
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Ganglioside GD3 Sensitizes Human Hepatoma Cells to Cancer Therapy*

Raquel ParísDagger §, Albert MoralesDagger §, Olga CollDagger , Alberto Sánchez-Reyes, Carmen García-RuizDagger ||**, and José C. Fernández-ChecaDagger ||Dagger Dagger §§

From the Dagger  Liver Unit, Instituto de Malalties Digestives,  Servicio de Radioterapia, Hospital Clinic i Provincial, Instituto Investigaciones Biomedicas August Pi Suñer and the Dagger Dagger  Department of Experimental Pathology, Instituto Investigaciones Biomédicas Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona 08036, Spain

Ganglioside GD3 (GD3) has emerged as a modulator of cell death pathways due to its ability to interact with mitochondria and disable survival pathways. Because NF-kappa B activation contributes to cancer therapy resistance, this study was undertaken to test whether GD3 modulates the response of human hepatoblastoma HepG2 cells to radio- and chemotherapy. NF-kappa B was activated in HepG2 cells shortly after therapeutic doses of ionizing radiation or daunorubicin treatment that translated into up-regulation of kappa B-dependent genes. These effects were accompanied by minimal killing of HepG2 cells by either ionizing radiation or daunorubicin. However, GD3 pretreatment blocked the nuclear translocation of active kappa B members, without effect on Akt phosphorylation, induced by either treatment. The suppression of kappa B-dependent gene induction by GD3 was accompanied by enhanced apoptotic cell death caused by these therapies. Furthermore, the combination of GD3 plus ionizing radiation stimulated the formation of reactive species followed by the mitochondrial release of cytochrome c and Smac/Diablo and caspase 3 activation. Pretreatment with cyclosporin A before radiotherapy protected HepG2 cells from the therapeutic combination of GD3 plus ionizing radiation. These findings underscore a key role of mitochondria in the response of tumor cells to cancer therapy and highlight the potential relevance of GD3 to overcome resistance to cancer therapy by combining its dual action as a mitochondria-interacting and NF-kappa B-inactivating agent.

* This work was supported in part by the Research Center for Liver and Pancreatic Dieases (Grant P50-AA11999) funded by the National Institute on Alcohol Abuse and Alcoholism, Plan Nacional de I+D Grants SAF 99-0138, SAF2001-2118, and Fondo Investigaciones Sanitarias, FISS 00-907.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors have contributed equally to this work.

|| Both authors share senior authorship.

** An Sisteina Nacional de Salud investigator from the Fondo Investigaciones Sanitarias.

§§ To whom correspondence should be addressed. Tel.: 34-3-227-5709; Fax: 34-3-451-5272; E-mail: checa229@yahoo.com.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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