CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells.
Ligation of the cell surface molecule CD44 by anti-CD44 monoclonal antibodies (mAbs) has been shown to induce cell differentiation, cell growth inhibition and in some cases, apoptosis in myeloid leukemic cells. We report, herein, that exposure of human erythroleukemic HEL cells to the anti-CD44 mAb A3D8 resulted in cell growth inhibition followed by caspase-independent apoptosis-like cell death. This process was associated with the disruption of mitochondrial membrane potential (Delta Psi m), the mitochondrial release of apoptosis-inducing factor (AIF), but not of cytochrome c, and the nuclear translocation of AIF. All these effects including cell death, loss of mitochondrial Delta Psi m and AIF release were blocked by pretreatment with the poly (ADP-ribose) polymerase inhibitor isoquinoline. A significant protection against cell death was also observed by using small interfering RNA for AIF. Moreover, we show that calpain protease was activated before the appearance of apoptosis, and that calpain inhibitors or transfection of calpain-siRNA decrease A3D8-induced cell death, and block AIF release. These data suggest that CD44 ligation triggers a novel caspase-independent cell death pathway via calpain-dependent AIF release in erythroleukemic HEL cells.
Artus
C
C
INSERM U602, Hôpital Paul Brousse, Villejuif, France.
Maquarre
E
E
Moubarak
R S
RS
Delettre
C
C
Jasmin
C
C
Susin
S A
SA
Robert-Lézénès
J
J
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D045304:Cytochromes c / Q000032:analysis; D004273:DNA, Neoplasm / Q000302:isolation & purification; D016521:Electrophoresis, Gel, Pulsed-Field; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D008564:Membrane Potentials; D051336:Mitochondrial Membranes / Q000502:physiology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
C494829:AIFM1 protein, human; D015703:Antigens, CD; D051033:Apoptosis Inducing Factor; D004273:DNA, Neoplasm; D018960:Hyaluronan Receptors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D045304:Cytochromes c; D002154:Calpain; D020169:Caspases; C039109:isoquinoline