CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily.
CD40, a tumor necrosis factor (TNF) receptor (TNFR) family member, conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. The ability of CD40 to mediate apoptosis in carcinoma cells is intriguing given the fact that the CD40 cytoplasmic C terminus lacks a death domain homology with the cytotoxic members of the TNFR superfamily, such as Fas, TNFR1, and TNF-related apoptosis-inducing ligand (TRAIL) receptors. In this study, we have probed the mechanism by which CD40 transduces death signals. Using a trimeric recombinant soluble CD40 ligand to activate CD40, we have found that this phenomenon critically depends on the membrane proximal domain (amino acids 216 to 239) but not the TNFR-associated factor-interacting PXQXT motif in the CD40 cytoplasmic tail. CD40-mediated cytotoxicity is blocked by caspase inhibitors, such as zVAD-fmk and crmA, and involves activation of caspase 8 and caspase 3. Interestingly, CD40 ligation was found to induce functional Fas ligand, TRAIL (Apo-2L) and TNF in apoptosis-susceptible carcinoma cells and to up-regulate expression of Fas. These findings identify a novel proapoptotic mechanism which is induced by CD40 in carcinoma cells and depends on the endogenous production of cytotoxic cytokines and autocrine or paracrine induction of cell death.
Eliopoulos
A G
AG
CRC Institute for Cancer Studies, The University of Birmingham Medical School, Birmingham B15 2TT, United Kingdom. A.G.Eliopoulos@bham.ac.uk
Davies
C
C
Knox
P G
PG
Gallagher
N J
NJ
Afford
S C
SC
Adams
D H
DH
Young
L S
LS
D020816:Amino Acid Motifs; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014764:Viral Proteins; D019014:fas Receptor / Q000378:metabolism
D019013:CD40 Antigens; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019014:fas Receptor; D023201:CD40 Ligand; C074641:interleukin-1beta-converting enzyme inhibitor; D003513:Cycloheximide; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases