The effect of microenvironmental CD40 signals on TRAIL- and drug-induced apoptosis in follicular lymphoma cells.
Follicular lymphoma (FL) cells are malignant counterparts of germinal centre (GC) B cells. Microenvironment of FL B cells has an important role in the progression of FL and might also have an impact on the treatment of FL. CD40 is an important mediator of microenvironmental survival signals in GCs. Here we studied responses of CD40 signalling on TRAIL-, dexamethasone- and doxorubicin-induced apoptosis in three human FL cell lines. In two of the FL cell lines, CD40 protected cells from apoptosis which was entirely dependent on the activation of NF-kappaB. In one of the FL cell lines, CD40 induced apoptosis itself. However, inhibition of NF-kappaB induced apoptosis in all three FL cell lines. Therefore, our results indicate that inhibitors of NF-kappaB or critical downstream anti-apoptotic targets of NF-kappaB instead of blocking CD40 antibodies in combination with TRAIL or other cytotoxic agents should be considered in the treatment of FL in order to prevent the protective effect of the microenvironment.
Nuutinen
U
U
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Kuopio, Kuopio. ulla-maija.nuutinen@uku.fi
Ropponen
A
A
Eeva
J
J
Eray
M
M
Pellinen
R
R
Wahlfors
J
J
Pelkonen
J
J
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008224:Lymphoma, Follicular / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D000975:Antioxidants; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019013:CD40 Antigens; D005938:Glucocorticoids; D007093:Imidazoles; D016328:NF-kappa B; D011810:Quinoxalines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013859:Thiocarbamates; D051020:bcl-X Protein; C066229:prolinedithiocarbamate; D003907:Dexamethasone; D004317:Doxorubicin; D011392:Proline; D051550:I-kappa B Kinase