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

Apoptosis. 2009 May;14(5):687-98. doi: 10.1007/s10495-009-0337-7.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Murine-Derived
  • Apoptosis / drug effects*
  • CD40 Antigens / metabolism
  • Caspase 9 / metabolism*
  • Cell Line, Tumor
  • Cytochromes c / metabolism
  • Enzyme Activation / drug effects
  • Humans
  • Kinetics
  • Lymphoma, Follicular / enzymology*
  • Lymphoma, Follicular / pathology*
  • Mitochondria / drug effects*
  • Mitochondria / enzymology*
  • Receptors, Death Domain / metabolism
  • Rituximab
  • bcl-X Protein / metabolism
  • fas Receptor / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • CD40 Antigens
  • Receptors, Death Domain
  • bcl-X Protein
  • fas Receptor
  • Rituximab
  • Cytochromes c
  • Caspase 9