The involvement of mitochondria and the caspase-9 activation pathway in rituximab-induced apoptosis in FL cells.
Despite the wide use of anti-CD20 antibody rituximab in the cancer treatment of B cell malignancies, the signalling pathways of CD20-induced apoptosis are still not understood. By using dominant negative (DN)-caspase-9 overexpressing follicular lymphoma cells we demonstrated that the activation of caspase-9 was essential for rituximab-mediated apoptosis. The death receptor pathway mediated by caspase-8 activation was not involved in rituximab-mediated apoptosis since overexpression of FLIP(short) or FLIP(long) proteins, inhibitors of caspase-8 activation, could not inhibit rituximab-induced apoptosis. However, the death receptor pathway activation by anti-Fas antibodies showed an additive effect on rituximab-induced apoptosis. The stabilisation of the mitochondrial outer membrane by Bcl-x(L) overexpression inhibited cell death, showing the important role of mitochondria in rituximab-induced apoptosis. Interestingly, the rituximab-induced release of cytochrome c and collapse of mitochondrial membrane potential were regulated by caspase-9. We suggest that caspase-9 and downstream caspases may feed back to mitochondria to amplify mitochondrial disruption during intrinsic apoptosis.
Eeva
Jonna
J
Department of Clinical Microbiology, University of Kuopio, Yliopistoranta 1C, 70210, Kuopio, Finland. eeva@hytti.uku.fi
Nuutinen
Ulla
U
Ropponen
Antti
A
Mättö
Mikko
M
Eray
Mine
M
Pellinen
Riikka
R
Wahlfors
Jarmo
J
Pelkonen
Jukka
J
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects*; D019013:CD40 Antigens / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008224:Lymphoma, Follicular / Q000201:enzymology* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D053218:Receptors, Death Domain / Q000378:metabolism; D000069283:Rituximab; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D019013:CD40 Antigens; D053218:Receptors, Death Domain; D051020:bcl-X Protein; D019014:fas Receptor; D000069283:Rituximab; D045304:Cytochromes c; D053453:Caspase 9