GD3, an overexpressed tumor-derived ganglioside, mediates the apoptosis of activated but not resting T cells

Cancer Res. 2009 Apr 1;69(7):3095-104. doi: 10.1158/0008-5472.CAN-08-3776. Epub 2009 Mar 10.

Abstract

We previously elucidated an important role for gangliosides in renal cell carcinoma-mediated T lymphocyte apoptosis, although the mechanism by which they mediated lymphocyte death remained unclear. Here, we show that when added in purified form, GD3 is internalized by activated T cells, initiating a series of proapoptotic events, including the induction of reactive oxygen species (ROS), an enhancement of p53 and Bax accumulation, an increase in mitochondrial permeability, cytochrome c release, and the activation of caspase-9. GD3-induced apoptosis of activated T cells was dose dependent and inhibitable by pretreating the lymphocytes with N-acetylcysteine, cyclosporin A, or bongkrekic acid, emphasizing the essential role of ROS and mitochondrial permeability to the process. Ganglioside-induced T-cell killing was associated with the caspase-dependent degradation of nuclear factor-kappaB-inducible, antiapoptotic proteins, including RelA; this suggests that their loss is initiated only after the cascade is activated and that their disappearance amplifies but not triggers GD3 susceptibility. Resting T cells did not internalize appreciable levels of GD3 and did not undergo any of the proapoptotic changes that characterize activated T lymphocytes exposed to the ganglioside. RelA overexpression endows Jurkat cells with resistance to GD3-mediated apoptosis, verifying the role of the intact transcription factor in mediating protection from the ganglioside.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcysteine / pharmacology
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Caspase Inhibitors
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cytochromes c / immunology
  • Cytochromes c / metabolism
  • Gangliosides / immunology*
  • Gangliosides / pharmacokinetics
  • Glioblastoma / immunology
  • Glioblastoma / pathology
  • Humans
  • Jurkat Cells
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / pathology
  • Lymphocyte Activation
  • Mitochondrial Membranes / metabolism
  • Reactive Oxygen Species / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Antioxidants
  • Caspase Inhibitors
  • Gangliosides
  • Reactive Oxygen Species
  • ganglioside, GD3
  • Cytochromes c
  • CASP8 protein, human
  • Caspase 8
  • Caspase 9
  • Acetylcysteine