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Apoptosis-resistant mitochondria in T cells selected for resistance to Fas signaling

G Q Wang1, B R Gastman, E Wieckowski

  • 1Department of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.

The Journal of Biological Chemistry
|November 7, 2000
PubMed

Insights

Jurkat cells resistant to Fas-induced apoptosis also resist chemotherapy drugs. This resistance stems from a mitochondrial defect in releasing proteins crucial for cell death, suggesting shared apoptosis pathway regulators.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Jurkat leukemic T cells undergo apoptosis via extrinsic (death receptor) and intrinsic (mitochondrial) pathways.
  • Resistance to apoptosis is a hallmark of cancer and a challenge in chemotherapy.

Purpose of the Study:

  • To investigate the mechanisms of apoptosis resistance in Jurkat cells selected for resistance to Fas-induced cell death.
  • To determine if resistance to extrinsic apoptosis pathways confers cross-resistance to intrinsic apoptosis pathways.

Main Methods:

  • Selection of Jurkat cell lines resistant to Fas-mediated apoptosis.
  • Treatment of resistant and wild-type cells with apoptosis-inducing agents (Fas cross-linking, VP-16, staurosporine).
  • Analysis of caspase activity, mitochondrial integrity, and release of apoptotic factors (cytochrome c, apoptosis-inducing factor).

Main Results:

  • Fas-resistant Jurkat cells exhibited cross-resistance to VP-16 and staurosporine, indicating blocked apoptosis at an apical phase.
  • Resistant cells showed no caspase activation and no mitochondrial alterations (permeability transition, cardiolipin loss, ROS generation, cytochrome c release) upon VP-16 treatment.
  • Mitochondria from resistant cells failed to release cytochrome c or apoptosis-inducing factor in response to Bax or truncated Bid.

Conclusions:

  • A defect in the mitochondria's ability to release intermembrane proteins in response to Bid or Bax mediates resistance to chemotherapeutic drugs.
  • This mitochondrial defect represents a novel mechanism of apoptosis resistance.
  • Shared regulatory components between extrinsic and intrinsic apoptosis pathways may exist, as suggested by the cross-resistance observed.

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