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Title

Ganglioside GD3 sensitizes human hepatoma cells to cancer therapy

AuthorsParís, Raquel; Morales, Albert ; Coll, Olga; Sánchez-Reyes, Alberto; García-Ruiz, Carmen ; Fernández-Checa, José C.
Issue Date20-Dec-2002
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 277(51): 49870-49876 (2002)
AbstractGanglioside 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-κB 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-κB was activated in HepG2 cells shortly after therapeutic doses of ionizing radiation or daunorubicin treatment that translated into up-regulation of κB-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 κB members, without effect on Akt phosphorylation, induced by either treatment. The suppression of κB-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-κB-inactivating agent.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M208303200
URIhttp://hdl.handle.net/10261/111677
DOI10.1074/jbc.M208303200
Identifiersdoi: 10.1074/jbc.M208303200
issn: 0021-9258
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