Tumor-induced apoptosis of T cells

Amplification by a mitochondrial cascade

B. R. Gastman, Xiao-Ming Yin, D. E. Johnson, E. Wieckowski, G. Q. Wang, S. C. Watkins, H. Rabinowich

Research output: Contribution to journalArticle

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Abstract

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 aud 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.

Original languageEnglish (US)
Pages (from-to)6811-6817
Number of pages7
JournalCancer Research
Volume60
Issue number24
StatePublished - Dec 15 2000
Externally publishedYes

Fingerprint

Apoptosis
T-Lymphocytes
Mitochondria
Jurkat Cells
Anti-Idiotypic Antibodies
Neoplasms
Caspase 9
Permeability
Bongkrekic Acid
Cell Death
Fas Ligand Protein
Caspase 8
Etoposide
Caspases
Coculture Techniques
Cytochromes c
Caspase 3
Cytosol
Immunotherapy
Cyclosporine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gastman, B. R., Yin, X-M., Johnson, D. E., Wieckowski, E., Wang, G. Q., Watkins, S. C., & Rabinowich, H. (2000). Tumor-induced apoptosis of T cells: Amplification by a mitochondrial cascade. Cancer Research, 60(24), 6811-6817.

Tumor-induced apoptosis of T cells : Amplification by a mitochondrial cascade. / Gastman, B. R.; Yin, Xiao-Ming; Johnson, D. E.; Wieckowski, E.; Wang, G. Q.; Watkins, S. C.; Rabinowich, H.

In: Cancer Research, Vol. 60, No. 24, 15.12.2000, p. 6811-6817.

Research output: Contribution to journalArticle

Gastman, BR, Yin, X-M, Johnson, DE, Wieckowski, E, Wang, GQ, Watkins, SC & Rabinowich, H 2000, 'Tumor-induced apoptosis of T cells: Amplification by a mitochondrial cascade', Cancer Research, vol. 60, no. 24, pp. 6811-6817.
Gastman BR, Yin X-M, Johnson DE, Wieckowski E, Wang GQ, Watkins SC et al. Tumor-induced apoptosis of T cells: Amplification by a mitochondrial cascade. Cancer Research. 2000 Dec 15;60(24):6811-6817.
Gastman, B. R. ; Yin, Xiao-Ming ; Johnson, D. E. ; Wieckowski, E. ; Wang, G. Q. ; Watkins, S. C. ; Rabinowich, H. / Tumor-induced apoptosis of T cells : Amplification by a mitochondrial cascade. In: Cancer Research. 2000 ; Vol. 60, No. 24. pp. 6811-6817.
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