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Lysosomal and mitochondrial pathways in miltefosine-induced apoptosis in U937 cells

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Abstract

Hexadecylphosphocholine (HePC) is an anticancer agent whose effect has been shown to involve apoptosis induction but the signaling pathways leading to apoptosis remain to be elucidated. We show here that HePC induces activation of caspase-9, -3, and -8 via the intrinsic pathway, release of cytochrome c, activation and relocation of Bax to the mitochondria as well as the cleavage of Bid. Moreover, a lysosomal pathway characterized by partial lysosomal rupture, cathepsin B activation and relocation from lysosomes to the cytosol, is involved in HePC-induced apoptosis. A cathepsin B/L inhibitor partially suppresses caspase activation and apoptosis induction, indicating signaling between lysosomes and mitochondria. Conversely, the pancaspase inhibitor Q-VD-OPH inhibits lysosomal rupture, but only at early time points, suggesting that immediate lysosomal rupture involves caspases. Overexpression of Bcl-2, an anti-apoptotic protein known to prevent mitochondrial dysfunction, totally abrogates lysosomal destabilization and cell death.

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Acknowledgments

We are grateful to FRM (Fondation pour la Recherche Médicale) for providing financial support to Caroline Paris. We thank Valérie Nicolas for her excellent assistance in confocal microscopy. INSERM U749 is an “Equipe labellisée par la Ligue Nationale contre le Cancer”.

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  1. INSERM U749, Faculté de Pharmacie Paris-Sud. 5, rue Jean-Baptiste Clément 92290, Châtenay-Malabry, France

    Caroline Paris, Jacques Bertoglio & Jacqueline Bréard

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  1. Caroline Paris
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  2. Jacques Bertoglio
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  3. Jacqueline Bréard
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Correspondence to Jacqueline Bréard.

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Paris, C., Bertoglio, J. & Bréard, J. Lysosomal and mitochondrial pathways in miltefosine-induced apoptosis in U937 cells. Apoptosis 12, 1257–1267 (2007). https://doi.org/10.1007/s10495-007-0052-1

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