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

Margaret E Tome1, Melba C Jaramillo, Margaret M Briehl

  • 1Department of Pathology, University of Arizona, Tucson, AZ 85724, USA. mtome@u.arizona.edu

Free Radical Biology & Medicine
|October 4, 2011
PubMed

Insights

Glucocorticoids induce apoptosis in lymphoma cells by increasing hydrogen peroxide (H2O2) levels. Overcoming H2O2 buildup is key to enhancing cancer treatment efficacy and overcoming drug resistance.

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Oncology

Background:

  • Glucocorticoids are used to treat hematologic malignancies by inducing apoptosis.
  • Understanding the molecular mechanisms of glucocorticoid-induced apoptosis is crucial for identifying and overcoming resistance.
  • Oxidative stress plays a role in cellular signaling pathways relevant to cancer treatment.

Purpose of the Study:

  • To investigate the role of hydrogen peroxide (H2O2) in glucocorticoid-induced apoptosis in lymphoid cells.
  • To identify mechanisms of resistance to glucocorticoid therapy.
  • To explore strategies for overcoming glucocorticoid resistance in hematologic malignancies.

Main Methods:

  • Treatment of WEHI7.2 murine thymic lymphoma cells and human leukemia cell lines with glucocorticoids.
  • Measurement of intracellular hydrogen peroxide ([H2O2]) levels and redox environment.
  • Assessment of apoptosis and clonogenicity following glucocorticoid treatment and intervention with PEG-catalase (PEG-CAT).
  • Analysis of cell lines engineered for H2O2 resistance (overexpressing catalase or selected for resistance).
  • Evaluation of survival signaling pathways (pERK) and the effect of MEK inhibitors.

Main Results:

  • Glucocorticoid treatment increased intracellular H2O2 and oxidized the redox environment in lymphoid cells prior to apoptosis.
  • Inhibition of H2O2 accumulation using PEG-CAT significantly increased cell clonogenicity, indicating reduced apoptosis.
  • Cells engineered for H2O2 resistance (high catalase activity or pre-selected resistance) exhibited significantly higher clonogenicity and maintained pro-survival ERK signaling.
  • MEK inhibition sensitized these resistant cells to glucocorticoid-induced apoptosis.

Conclusions:

  • An increase in hydrogen peroxide (H2O2) is a necessary event for glucocorticoid-induced apoptosis in lymphoid cells.
  • Mechanisms that increase H2O2 removal lead to resistance against glucocorticoid-induced apoptosis.
  • Targeting MEK signaling can overcome resistance in cells that are resistant to glucocorticoids due to oxidative stress pathways.

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