Lysosomal and mitochondrial pathways in miltefosine-induced apoptosis in U937 cells.
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.
Paris
Caroline
C
INSERM U749, Faculté de Pharmacie Paris-Sud. 5, rue Jean-Baptiste Clément 92290, Châtenay-Malabry, France.
Bertoglio
Jacques
J
Bréard
Jacqueline
J
D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000378:metabolism; D013347:Subcellular Fractions; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D011480:Protease Inhibitors; D051028:bcl-2-Associated X Protein; D010767:Phosphorylcholine; C039128:miltefosine; D002403:Cathepsins; D020169:Caspases