The involvement of mitochondria and the caspase-9 activation pathway in rituximab-induced apoptosis in FL cells
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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 FLIPshort or FLIPlong 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-xL 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.
KeywordsCD20 Apoptosis Caspase-9 Bcl-xL Cytochrome c Follicular lymphoma
This work was supported by the Finnish Medical Foundation and Kuopio Univesity Hospital Grants. We thank Eila Pelkonen, Riitta Korhonen and Katja Häkkinen for their excellent technical assistance. We thank Dr Tapio Nousiainen and Kuopio University Hospital for the anti-CD20 antibody rituximab (Mabthera®).