title: CD44 ligation induces apoptosis via caspase- and serine protease-dependent pathways in acute promyelocytic leukemia cells.
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 DeltaPsi m 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.
authors.affiliation: INSERM U602, Hôpital Paul Brousse, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Maquarre
authors.forename: C
authors.initials: C
authors.lastname: Artus
authors.forename: Z
authors.initials: Z
authors.lastname: Gadhoum
authors.forename: C
authors.initials: C
authors.lastname: Jasmin
authors.forename: F
authors.initials: F
authors.lastname: Smadja-Joffe
authors.forename: J
authors.initials: J
authors.lastname: Robert-Lézénès
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D008024:Ligands; D015842:Serine Proteinase Inhibitors; D014212:Tretinoin; D012697:Serine Endopeptidases; D020169:Caspases