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J. Biol. Chem., Vol. 278, Issue 46, 45200-45208, November 14, 2003

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Two Distinct Gb3/CD77 Signaling Pathways Leading to Apoptosis Are Triggered by Anti-Gb3/CD77 mAb and Verotoxin-1^*

Cécile Tétaud, Thomas Falguières, Karine Carlier¶, Yann Lécluse||, Julie Garibal, Dominique Coulaud, Pierre Busson, Rudi Steffensen**, Henrik Clausen**, Ludger Johannes, and Joëlle Wiels

From the Laboratoire Interactions Moléculaires et Cancer, CNRS UMR 8126, Institut Gustave Roussy, 94805 Villejuif cedex, France, the Unité Mixte de Recherche 144, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France, the ^||Service Commun de Cytométrie, Institut Fédératif de Recherche 54, Institut Gustave Roussy, 94805 Villejuif cedex, France, and the ^**School of Dentistry, University of Copenhagen, Norre Allé 20, 2200 Copenhagen N, Denmark

Globotriasosylceramide (Gb3), a neutral glycosphingolipid, is the B-cell differentiation antigen CD77 and acts as the receptor for most Shiga toxins, including verotoxin-1 (VT-1). We have shown that both anti-Gb3/CD77 mAb and VT-1 induce apoptosis in Burkitt's lymphoma cells. We compared the apoptotic pathways induced by these two molecules by selecting cell lines sensitive to only one of these inducers or to both. In all these cell lines (including the apoptosis-resistant line), VT-1 was transported to the endoplasmic reticulum and inhibited protein synthesis similarly, suggesting that VT-1-induced apoptosis is dissociated from these processes. VT-1 triggered a caspase- and mitochondria-dependent pathway (rapid activation of caspases 8 and 3 associated with a loss of mitochondrial membrane potential (_m) and the release of cytochrome c from mitochondria). In contrast, the anti-Gb3/CD77 mAb-induced pathway was caspase-independent and only involved partial depolarization of mitochondria. Antioxidant compounds had only marginal effects on VT-1-induced apoptosis but strongly protected cells from anti-Gb3/CD77 mAb-induced apoptosis. VT-1- and anti-Gb3/CD77 mAb-treated cells displayed very different features on electron microscopy. These results clearly indicate that the binding of different ligands to Gb3/CD77 triggers completely different apoptotic pathways.

Received for publication, April 14, 2003 , and in revised form, August 26, 2003.

^* This work was supported in part by grants from the Association pour la Recherche sur le Cancer (ARC 4213), the Ministère de la Recherche et des Nouvelles Technologies (ACI jeunes chercheurs-5223), and the Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Holds a doctoral fellowship from the Ligue Nationale Française contre le Cancer.

To whom correspondence should be addressed. Tel.: 33-1-42-11-47-40; Fax: 33-1-42-11-54-94; E-mail: wiels{at}igr.fr.

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