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Apoptosis

, Volume 14, Issue 5, pp 687–698 | Cite as

The involvement of mitochondria and the caspase-9 activation pathway in rituximab-induced apoptosis in FL cells

  • Jonna Eeva
  • Ulla Nuutinen
  • Antti Ropponen
  • Mikko Mättö
  • Mine Eray
  • Riikka Pellinen
  • Jarmo Wahlfors
  • Jukka Pelkonen
Original Paper

Abstract

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.

Keywords

CD20 Apoptosis Caspase-9 Bcl-xL Cytochrome c Follicular lymphoma 

Notes

Acknowledgments

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®).

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jonna Eeva
    • 1
  • Ulla Nuutinen
    • 1
  • Antti Ropponen
    • 1
  • Mikko Mättö
    • 2
  • Mine Eray
    • 3
  • Riikka Pellinen
    • 4
  • Jarmo Wahlfors
    • 5
  • Jukka Pelkonen
    • 1
    • 6
  1. 1.Department of Clinical MicrobiologyUniversity of KuopioKuopioFinland
  2. 2.Department of Clinical ChemistryKuopio University HospitalKuopioFinland
  3. 3.Department of Pathology, Haartman InstituteUniversity of HelsinkiHelsinkiFinland
  4. 4.Department of PharmaceuticsUniversity of KuopioKuopioFinland
  5. 5.Academic Development UnitUniversity of TampereTampereFinland
  6. 6.Department of Clinical MicrobiologyKuopio University HospitalKuopioFinland

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