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 Gastman, B. R. Articles by Rabinowich, H. Search for Related Content PubMed PubMed Citation Articles by Gastman, B. R. Articles by Rabinowich, H.

Tumor-induced Apoptosis of T Cells: Amplification by a Mitochondrial Cascade¹

Departments of Otolaryngology [B. R. G.], Pathology [X-M. Y., E. W., G-Q. W., H. R.], Pharmacology [D. E. J.], Medicine [D. E. J.], and Cell Biology and Physiology [S. C. W.], University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute [X-M. Y., D. E. J., S. C. W., H. R.], Pittsburgh, Pennsylvania 15213

We have recently reported that apoptosis of T cells induced by squamous cell carcinoma of the head and neck (SCCHN) is partly Fas dependent. This tumor-induced T-cell death is mediated by the activities of caspase-8 and caspase-3 and is partially inhibited by antibodies to either Fas or Fas ligand. We report here that in contrast to apoptosis induced by agonistic anti-Fas antibody (Ab), the tumor-induced apoptotic cascade in Jurkat cells is significantly amplified by a mitochondrial loop. The involvement of mitochondria in tumor-induced apoptosis of T cells was demonstrated by changes in mitochondrial permeability transition as assessed by 3,3'-dihexiloxadicarbocyanine staining, by cleavage of cytosolic BID and its translocation to the mitochondria, by release of cytochrome c to the cytosol, and by the presence of active subunits of caspase-9 in Jurkat T cells cocultured with tumor cells. To further elucidate the significance of mitochondria in tumor-induced T-cell death, we investigated the effects of various inhibitors of the mitochondrial pathway. Specific antioxidants, as well as two inhibitors of mitochondria permeability transition, bongkrekic acid and cyclosporin A, significantly blocked the DNA degradation induced in Jurkat T cells by SCCHN cells. However, these inhibitors had no effect on cells triggered by anti-Fas Ab. Furthermore, a cell-permeable inhibitor of caspase-9, Ac-LEHD.CHO, which did not inhibit T-cell apoptosis induced by anti-Fas Ab, markedly inhibited apoptosis induced by etoposide or by coculture of Jurkat with SCCHN cells. These findings demonstrate that apoptotic cascades induced in Jurkat T lymphocytes by anti-Fas Ab or tumor cells are differentially susceptible to a panel of inhibitors of mitochondrial apoptotic events. It appears that besides the Fas-mediated pathway, additional mitochondria-dependent cascades are involved in apoptosis of tumor-associated lymphocytes. Inhibition of mitochondria-dependent cascades of caspase activation should be considered to enhance the success of immunotherapy or vaccination protocols in cancer.

This article has been cited by other articles:

				H. Li, X. Cai, X. Fan, B. Moquin, C. Stoicov, and J. Houghton Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells Am J Physiol Gastrointest Liver Physiol, January 1, 2008; 294(1): G263 - G275. [Abstract] [Full Text] [PDF]

				P. Legembre, S. Daburon, P. Moreau, F. Ichas, F. de Giorgi, J.-F. Moreau, and J.-L. Taupin Amplification of Fas-Mediated Apoptosis in Type II Cells via Microdomain Recruitment Mol. Cell. Biol., August 1, 2005; 25(15): 6811 - 6820. [Abstract] [Full Text] [PDF]

				C. Batandier, X. Leverve, and E. Fontaine Opening of the Mitochondrial Permeability Transition Pore Induces Reactive Oxygen Species Production at the Level of the Respiratory Chain Complex I J. Biol. Chem., April 23, 2004; 279(17): 17197 - 17204. [Abstract] [Full Text] [PDF]

				W.-S. Wu, Z.-X. Xu, W. N. Hittelman, P. Salomoni, P. P. Pandolfi, and K.-S. Chang Promyelocytic Leukemia Protein Sensitizes Tumor Necrosis Factor alpha -Induced Apoptosis by Inhibiting the NF-kappa B Survival Pathway J. Biol. Chem., March 28, 2003; 278(14): 12294 - 12304. [Abstract] [Full Text] [PDF]

				C. Chauvin, F. De Oliveira, X. Ronot, M. Mousseau, X. Leverve, and E. Fontaine Rotenone Inhibits the Mitochondrial Permeability Transition-induced Cell Death in U937 and KB Cells J. Biol. Chem., October 26, 2001; 276(44): 41394 - 41398. [Abstract] [Full Text] [PDF]