Lysosomal and mitochondrial pathways in miltefosine-induced apoptosis in U937 cells |
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Authors: | Caroline Paris Jacques Bertoglio Jacqueline Bréard |
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Institution: | (1) INSERM U749, Faculté de Pharmacie Paris-Sud. 5, rue Jean-Baptiste Clément 92290, Chatenay-Malabry, France |
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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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Keywords: | Miltefosine Apoptosis Caspase Cathepsin Lysosome Mitochondria |
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