Resistance to radiation-induced apoptosis in Bcl-2-expressing cells is reversed by depleting cellular thiols

Nena Mirkovic, David W. Voehringer, Michael D. Story, David J. McConkey, Timothy J. McDonnell, Raymond E. Meyn

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanism by which Bcl-2 oncogene expression inhibits radiation-induced apoptosis has been investigated in two mouse lymphoma cell lines: line LY-as is radiation sensitive, displays substantial radiaton-induced apoptosis, and expresses low levels of Bcl-2; line LY-ar is radiation-resistant, displays a low apoptosis propensity, and expresses 30-fold higher amount of Bcl-2 protein than does the sensitive line. We observed that upon incubation in cystine/methionine-free (C/M-) medium, radiation-induced apoptosis in the LY-ar cells was restored to levels comparable to that seen in the LY-as cells. Intracellular glutathione (GSH) concentrations in LY-ar cells incubated in C/M- medium plummeted to 50% of control values within 2 h. LY-ar cells treated with diethyl maleate (DEM) or diamide, agents that deplete cellular thiols, had increased susceptibility to radiation-induced apoptosis in a manner similar to C/M- medium. These results are consistent with the general idea that Bcl-2 expression blocks apoptosis through an antioxidant pathway that involves cellular thiols. That Bcl-2-expressing tumor cells can be sensitized by exogeneous agents that modify cellular thiols offers strategies for overcoming such resistance.

Original languageEnglish (US)
Pages (from-to)1461-1470
Number of pages10
JournalOncogene
Volume15
Issue number12
DOIs
StatePublished - 1997

Keywords

  • Antioxidants
  • Apoptosis
  • Bcl-2
  • Lymphoma
  • Radiation
  • Thiols

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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