A potential mechanism of rituximab-induced inhibition of tumor growth through its sensitization to tumor necrosis factor-related apoptosis-inducing ligand-expressing host cytotoxic cells

Leuk Lymphoma. 2011 Jan;52(1):108-21. doi: 10.3109/10428194.2010.531408. Epub 2010 Dec 6.


Rituximab (anti-CD20 mAb) mediates antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis in B-NHL cells. The contribution of other host-mediated cytotoxic effects has not been examined. The expression of death-inducing ligands (e.g. TRAIL) by host effector cells may contribute to the mechanism of tumor cell destruction in vivo by rituximab-mediated sensitization of resistant B-cell non-Hodgkin lymphoma (B-NHL) cells. We have examined the sensitizing activity of rituximab on B-NHL cell lines resistant to TRAIL (as model) and natural killer (NK)-induced apoptosis. Treatment of TRAIL-resistant B-NHL cell lines with rituximab sensitized the cells to TRAIL apoptosis and synergy was achieved via activation of the type II mitochondrial pathway for apoptosis. Further, rituximab (Fab')(2)-treated tumor cells were killed by purified peripheral blood-derived NK cells via TRAIL. Treatment of B-NHL cells with rituximab inhibited both YY1 DNA-binding activity and expression. Rituximab-mediated sensitization to TRAIL apoptosis was due, in large part, to rituximab-mediated inhibition of the transcription factor Yin Yang 1 (YY1). The direct role of YY1 in TRAIL sensitization by rituximab was shown in cells transfected with YY1 siRNA, and such cells mimicked rituximab and became sensitive to TRAIL-induced apoptosis. These data suggest that, in vivo, host effector cells expressing TRAIL may contribute to rituximab-mediated depletion of B-NHL cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Murine-Derived / therapeutic use*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • Electrophoretic Mobility Shift Assay
  • Flow Cytometry
  • Humans
  • Immunoenzyme Techniques
  • Lymphoma, B-Cell / metabolism*
  • Lymphoma, B-Cell / pathology
  • Lymphoma, B-Cell / prevention & control*
  • Membrane Potential, Mitochondrial / drug effects
  • RNA, Small Interfering / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • Rituximab
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Tumor Cells, Cultured
  • YY1 Transcription Factor / antagonists & inhibitors
  • YY1 Transcription Factor / genetics
  • YY1 Transcription Factor / metabolism


  • Antibodies, Monoclonal, Murine-Derived
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • YY1 Transcription Factor
  • YY1 protein, human
  • Rituximab