This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kudo, D. Articles by Finke, J. H. Search for Related Content PubMed PubMed Citation Articles by Kudo, D. Articles by Finke, J. H.

Gangliosides Expressed by the Renal Cell Carcinoma Cell Line SK-RC-45 Are Involved in Tumor-induced Apoptosis of T Cells¹

Departments of Immunology [D. K., P. R., M. T., C. T., J. H. F.] and Cell Biology [C. H., M. C.] in the Lerner Research Institute, Experimental Therapeutics [R. M. B., J. H. F.], and Urological Institute [R. M. B., J. H. F.], Cleveland Clinic Foundation, Cleveland, Ohio 44195

It is now understood that the genetic plasticity of cancer cells can lead to alterations that confer selective growth advantages to the tumor, some of which play a role in immune escape. A number of mutations veiling tumor cells from host immune defenses have been well characterized but more recent studies suggest that a variety of tumors can also express products that are actually toxic for the immune effectors. A component of this tumor-induced T-cell death has been attributed to receptor-mediated apoptosis. Some tumors, however, synthesize soluble factors that mediate similar effects. In this regard, we previously showed that supernatants from explanted renal cell carcinoma (RCC) tumors sensitized normal T cells to activation induced cell death, and the responsible products had the features of gangliosides. We have also shown that renal tumor lines, including SK-RC-45, induce apoptosis of both Jurkat cells and normal T lymphocytes. Here, we used the ganglioside synthesis inhibitor PPPP to define the role of gangliosides in RCC cell line (SK-RC-45)-mediated T cell and Jurkat cell apoptosis and to elucidate the proapoptotic molecular events by which the glycosphingolipids produce their effects. The ganglioside-synthesizing SK-RC-45 line stimulated the TUNEL (terminal deoxynucleotidyl transferase-mediated nick end labeling) positivity of cocultured T cells by a mechanism that involved decreasing lymphocyte expression levels of Bcl-2 and Bcl-_XL, inducing cytochrome c release from their mitochondria and activating caspases 9 and 3. These proapoptotic events were partially or completely abrogated when tumor cells were pretreated with PPPP for 5 days before the SK-RC-45/T lymphocyte coincubation, a regimen that reduced tumor-associated ganglioside levels by 70–80%. Our results suggest that gangliosides may be key mediators of RCC-induced T-cell apoptosis and imply that they contribute to the T-cell dysfunction in the tumor microenvironment.

This article has been cited by other articles:

				T. Das, G. Sa, E. Paszkiewicz-Kozik, C. Hilston, L. Molto, P. Rayman, D. Kudo, K. Biswas, R. M. Bukowski, J. H. Finke, et al. Renal Cell Carcinoma Tumors Induce T Cell Apoptosis through Receptor-Dependent and Receptor-Independent Pathways J. Immunol., April 1, 2008; 180(7): 4687 - 4696. [Abstract] [Full Text] [PDF]

				T. Das, G. Sa, C. Hilston, D. Kudo, P. Rayman, K. Biswas, L. Molto, R. Bukowski, B. Rini, J. H. Finke, et al. GM1 and Tumor Necrosis Factor-{alpha}, Overexpressed in Renal Cell Carcinoma, Synergize to Induce T-Cell Apoptosis Cancer Res., March 15, 2008; 68(6): 2014 - 2023. [Abstract] [Full Text] [PDF]

				G. Raval, S. Biswas, P. Rayman, K. Biswas, G. Sa, S. Ghosh, M. Thornton, C. Hilston, T. Das, R. Bukowski, et al. TNF-{alpha} Induction of GM2 Expression on Renal Cell Carcinomas Promotes T Cell Dysfunction J. Immunol., May 15, 2007; 178(10): 6642 - 6652. [Abstract] [Full Text] [PDF]

				R. H. Thompson, H. Dong, C. M. Lohse, B. C. Leibovich, M. L. Blute, J. C. Cheville, and E. D. Kwon PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma Clin. Cancer Res., March 15, 2007; 13(6): 1757 - 1761. [Abstract] [Full Text] [PDF]

				R. H. Thompson, H. Dong, and E. D. Kwon Implications of B7-H1 Expression in Clear Cell Carcinoma of the Kidney for Prognostication and Therapy Clin. Cancer Res., January 15, 2007; 13(2): 709s - 715s. [Abstract] [Full Text] [PDF]

				M. R. Gabri, Z. Mazorra, G. V. Ripoll, C. Mesa, L. E. Fernandez, D. E. Gomez, and D. F. Alonso Complete Antitumor Protection by Perioperative Immunization with GM3/VSSP Vaccine in a Preclinical Mouse Melanoma Model Clin. Cancer Res., December 1, 2006; 12(23): 7092 - 7098. [Abstract] [Full Text] [PDF]

				R. H. Thompson, S. M. Kuntz, B. C. Leibovich, H. Dong, C. M. Lohse, W. S. Webster, S. Sengupta, I. Frank, A. S. Parker, H. Zincke, et al. Tumor B7-H1 Is Associated with Poor Prognosis in Renal Cell Carcinoma Patients with Long-term Follow-up. Cancer Res., April 1, 2006; 66(7): 3381 - 3385. [Abstract] [Full Text] [PDF]

				M. Margalit, S. A. Ghazala, R. Alper, E. Elinav, A. Klein, V. Doviner, Y. Sherman, B. Thalenfeld, D. Engelhardt, E. Rabbani, et al. Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G917 - G925. [Abstract] [Full Text] [PDF]

				A. Chahlavi, P. Rayman, A. L. Richmond, K. Biswas, R. Zhang, M. Vogelbaum, C. Tannenbaum, G. Barnett, and J. H. Finke Glioblastomas Induce T-Lymphocyte Death by Two Distinct Pathways Involving Gangliosides and CD70 Cancer Res., June 15, 2005; 65(12): 5428 - 5438. [Abstract] [Full Text] [PDF]

				T. Ogushi, S. Takahashi, T. Takeuchi, T. Urano, K. Horie-Inoue, J. Kumagai, T. Kitamura, Y. Ouchi, M. Muramatsu, and S. Inoue Estrogen Receptor-Binding Fragment-Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma Cancer Res., May 1, 2005; 65(9): 3700 - 3706. [Abstract] [Full Text] [PDF]

				M. V. Thornton, D. Kudo, P. Rayman, C. Horton, L. Molto, M. K. Cathcart, C. Ng, E. Paszkiewicz-Kozik, R. Bukowski, I. Derweesh, et al. Degradation of NF-{kappa}B in T Cells by Gangliosides Expressed on Renal Cell Carcinomas J. Immunol., March 15, 2004; 172(6): 3480 - 3490. [Abstract] [Full Text] [PDF]

				X. Zhang and F. L. Kiechle Glycosphingolipids in Health and Disease Ann. Clin. Lab. Sci., January 1, 2004; 34(1): 3 - 13. [Abstract] [Full Text] [PDF]

				L. Molto, P. Rayman, E. Paszkiewicz-Kozik, M. Thornton, L. Reese, J. C. Thomas, T. Das, D. Kudo, R. Bukowski, J. Finke, et al. The Bcl-2 Transgene Protects T Cells from Renal Cell Carcinoma-mediated Apoptosis Clin. Cancer Res., September 15, 2003; 9(11): 4060 - 4068. [Abstract] [Full Text] [PDF]