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Apoptosis

CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells

Leukemia volume 19, pages 2296–2303 (2005)Cite this article

Abstract

We have recently reported that ligation of the CD44 cell surface antigen with A3D8 monoclonal antibody (mAb) triggers incomplete differentiation and apoptosis of the acute promyelocytic leukemia (APL)-derived NB4 cells. The present study characterizes the mechanisms underlying the apoptotic effect of A3D8 in NB4 cells. We show that A3D8 induces activation of both initiator caspase-8 and -9 and effector caspase-3 and -7 but only inhibition of caspase-3/7 and caspase-8 reduces A3D8-induced apoptosis. Moreover, A3D8 induces mitochondrial alterations (decrease in mitochondrial membrane potential ΔΨm and cytochrome c release), which are reduced by caspase-8 inhibitor, suggesting that caspase-8 is primarily involved in A3D8-induced apoptosis of NB4 cells. However, the apoptotic process is independent of TNF-family death receptor signalling. Interestingly, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) decreases A3D8-induced apoptosis and when combined with general caspase inhibitor displays an additive effect resulting in complete prevention of apoptosis. These results suggest that both caspase-dependent and serine protease-dependent pathways contribute to A3D8-induced apoptosis. Finally, A3D8 induces apoptosis in all-trans-retinoic acid-resistant NB4-derived cells and in APL primary blasts, characterizing the A3D8 anti-CD44 mAb as a novel class of apoptosis-inducing agent in APL.

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Acknowledgements

This work was supported by grants from the Association NRB-Vaincre le Cancer, the Leukemia-Lymphoma Society of America, the Fondation de France and the Association pour la Recherche sur le Cancer (ARC).

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Author notes

  1. E Maquarre and C Artus: These authors contributed equally to this work

Authors and Affiliations

  1. INSERM U602, Hôpital Paul Brousse, Villejuif, France

    E Maquarre, C Artus, C Jasmin & J Robert-Lézénès

  2. INSERM U718, Hôpital Saint-Louis, Paris, France

    E Maquarre, Z Gadhoum & F Smadja-Joffe

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  1. E Maquarre
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  2. C Artus
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Correspondence to J Robert-Lézénès.

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Maquarre, E., Artus, C., Gadhoum, Z. et al. CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells. Leukemia 19, 2296–2303 (2005). https://doi.org/10.1038/sj.leu.2403944

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