Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells

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19 Scopus citations

Abstract

Glucocorticoid-induced apoptosis is exploited clinically for the treatment of hematologic malignancies. Determining the required molecular events for glucocorticoid-induced apoptosis will identify resistance mechanisms and suggest strategies for overcoming resistance. In this study, we found that glucocorticoid treatment of WEHI7.2 murine thymic lymphoma cells increased the steady-state [H 2O 2] and oxidized the intracellular redox environment before cytochrome c release. Removal of glucocorticoids after the H 2O 2 increase resulted in a 30% clonogenicity; treatment with PEG-CAT increased clonogenicity to 65%. Human leukemia cell lines also showed increased H 2O 2 in response to glucocorticoids and attenuated apoptosis after PEG-CAT treatment. WEHI7.2 cells that overexpress catalase (CAT2, CAT38) or were selected for resistance to H 2O 2 (200R) removed enough of the H 2O 2 generated by glucocorticoids to prevent oxidation of the intracellular redox environment. CAT2, CAT38, and 200R cells showed a 90-100% clonogenicity. The resistant cells maintained pERK survival signaling in response to glucocorticoids, whereas the sensitive cells did not. Treating the resistant cells with a MEK inhibitor sensitized them to glucocorticoids. These data indicate that: (1) an increase in H 2O 2 is necessary for glucocorticoid-induced apoptosis in lymphoid cells, (2) increased H 2O 2 removal causes glucocorticoid resistance, and (3) MEK inhibition can sensitize oxidative stress-resistant cells to glucocorticoids.

Original languageEnglish (US)
Pages (from-to)2048-2059
Number of pages12
JournalFree Radical Biology and Medicine
Volume51
Issue number11
DOIs
StatePublished - Dec 1 2011

Keywords

  • Apoptosis
  • Catalase
  • ERK
  • Free radicals
  • Glucocorticoids
  • Glutathione
  • Hydrogen peroxide signaling
  • Lymphoma
  • MEK

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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