GD3, an Overexpressed Tumor-Derived Ganglioside, Mediates the Apoptosis of Activated but not Resting T Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 7; pp. 3095 - 3104
• Main Authors: SA, Gaurisankar, DAS, Tanya, MOON, Christina, HILSTON, Cynthia M, RAYMAN, Patricia A, RINI, Brian I, TANNENBAUM, Charles S, FINKE, James H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2009
• Subjects: Acetylcysteine - pharmacology; Antineoplastic agents; Antioxidants - pharmacology; Apoptosis - drug effects; Apoptosis - immunology; Biological and medical sciences; 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; Medical sciences; Mitochondrial Membranes - metabolism; Pharmacology. Drug treatments; Reactive Oxygen Species - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumors; Rest; Ganglioside; Cell death; T-Lymphocyte; Gene overexpression; Malignant tumor; Cancer; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3776

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.