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Type II anti-CD20 mAb-induced lysosome mediated cell death is mediated through a ceramide-dependent pathway

Hua Ren1, Chengwei Zhang1, Liwei Su1

  • 1Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.

Biochemical and Biophysical Research Communications
|January 21, 2015
PubMed

Insights

Type II anti-CD20 monoclonal antibodies (mAbs) induce programmed cell death (PCD) in lymphoma cells. Ceramide generation, downstream of homotypic adhesion, is essential for this caspase-independent cell death pathway.

Area of Science:

  • Immunology
  • Cell Biology
  • Oncology

Background:

  • Monoclonal antibodies (mAbs) have transformed non-Hodgkin lymphoma (NHL) treatment.
  • Mechanisms of mAb-induced programmed cell death (PCD) remain incompletely understood.
  • Type II anti-CD20 mAbs, like Tositumomab, induce PCD via a caspases-independent, lysosome-mediated pathway linked to homotypic adhesion (HA).

Purpose of the Study:

  • To elucidate the role of ceramide generation in mAb-induced PCD.
  • To investigate the molecular mechanisms linking homotypic adhesion, ceramide, and cell death.

Main Methods:

  • Utilized anti-CD20 mAbs in NHL cell lines.
  • Assessed programmed cell death (PCD) induction.
  • Investigated ceramide generation, homotypic adhesion (HA), and lysosome integrity.
  • Employed ceramide inhibition to determine its necessity in cell death.

Main Results:

  • Ceramide generation directly correlated with the ability of anti-CD20 mAbs to induce PCD.
  • Inhibiting ceramide производство abrogated Tositumomab-induced PCD, confirming ceramide's essential role.
  • Ceramide was generated downstream of mAb-induced HA and upstream of lysosome leakage.

Conclusions:

  • Ceramide generation is a critical mediator of PCD induced by type II anti-CD20 mAbs.
  • This pathway involves mAb-induced homotypic adhesion, followed by ceramide production and lysosome leakage.
  • This newly identified cell death pathway offers a potential target for eliminating malignant cells.
Keywords:
Burkitt's lymphomaCD20CeramideHomotypic adhesionLysosome leakageProgrammed cell death

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