Apoptosis-resistant Mitochondria in T Cells Selected for Resistance to Fas Signaling

Gui Qiang Wang, Brian R. Gastman, Eva Wieckowski, Leslie A. Goldstein, Asaf Rabinovitz, Xiao Ming Yin, Hannah Rabinowich

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Jurkat leukemic T cells are highly sensitive to the extrinsic pathways of apoptosis induced via the death receptor Fas or tumor necrosis factor-related apoptosis-inducing ligand as well as to the intrinsic/mitochondrial pathways of death induced by VP-16 or staurosporin. We report here that clonal Jurkat cell lines selected for resistance to Fas-induced apoptosis were cross-resistant to VP-16 or staurosporin. Each of the apoptotic pathways was blocked at an apical phase, where common regulators of apoptosis have not yet been defined. The Fas pathway was blocked at the level of caspase-8, whereas the intrinsic pathway was blocked at the mitochondria. No processing or activity of caspases was detected in resistant cells in response to either Fas-cross-linking or VP-16 treatment. Also, no apoptosis-associated alterations in the mitochondrial inner membrane, outer membrane, or matrix were detected in resistant Jurkat cells treated with VP-16. Thus, no changes in permeability transition, loss in inner membrane cardiolipin, generation of reactive oxygen species, or release of cytochrome c were observed in resistant cells treated with VP-16. Further, unlike purified mitochondria from wild type cells, those obtained from resistant cells did not release cytochrome c or apoptosis-inducing factor in response to recombinant Bax or truncated Bid. These results identify a defect in mitochondria ability to release intermembrane proteins in response to Bid or Bax as a mechanism of resistance to chemotherapeuetic drugs. Further, the selection of VP-16-resistant mitochondria via elimination of Fas-susceptible cells may suggest the existence of a shared regulatory component between the extrinsic and intrinsic pathways of apoptosis.

Original languageEnglish (US)
Pages (from-to)3610-3619
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number5
DOIs
StatePublished - Feb 2 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Apoptosis-resistant Mitochondria in T Cells Selected for Resistance to Fas Signaling'. Together they form a unique fingerprint.

  • Cite this

    Wang, G. Q., Gastman, B. R., Wieckowski, E., Goldstein, L. A., Rabinovitz, A., Yin, X. M., & Rabinowich, H. (2001). Apoptosis-resistant Mitochondria in T Cells Selected for Resistance to Fas Signaling. Journal of Biological Chemistry, 276(5), 3610-3619. https://doi.org/10.1074/jbc.M006222200