A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation.
Membrane-presented CD40 agonists can induce apoptosis in carcinoma, but not normal homologous epithelial cells, whereas soluble agonists are growth inhibitory but not proapoptotic unless protein synthesis is blocked. Here we demonstrate that membrane-presented CD40 ligand (CD154) (mCD40L), but not soluble agonists, triggers cell death in malignant human urothelial cells via a direct mechanism involving rapid upregulation of TNFR-associated factor (TRAF)3 protein, without concomitant upregulation of TRAF3 mRNA, followed by activation of the c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway and induction of the caspase-9/caspase-3-associated intrinsic apoptotic machinery. TRAF3 knockdown abrogated JNK/AP-1 activation and prevented CD40-mediated apoptosis, whereas restoration of CD40 expression in CD40-negative carcinoma cells restored apoptotic susceptibility via the TRAF3/AP-1-dependent mechanism. In normal human urothelial cells, mCD40L did not trigger apoptosis, but induced rapid downregulation of TRAF2 and 3, thereby paralleling the situation in B-lymphocytes. Thus, TRAF3 stabilization, JNK activation and caspase-9 induction define a novel pathway of CD40-mediated apoptosis in carcinoma cells.
Georgopoulos
N T
NT
Institute of Molecular Medicine, Epidemiology and Cancer Research, St James's University Hospital, Leeds LS9 7TF, UK.
Steele
L P
LP
Thomson
M J
MJ
Selby
P J
PJ
Southgate
J
J
Trejdosiewicz
L K
LK
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008024:Ligands; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012995:Solubility; D048008:TNF Receptor-Associated Factor 3; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014571:Urologic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D019459:Urothelium / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D019013:CD40 Antigens; D008024:Ligands; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D018808:Transcription Factor AP-1; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases