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Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells

Aaron L Miller1, Anna S Garza, Betty H Johnson

  • 1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1068, USA. aamiller@utmb.edu

Cancer Cell International
|March 30, 2007
PubMed
Abstract

Insights

Glucocorticoid resistance in lymphoid malignancies can be overcome by targeting mitogen-activated protein kinases (MAPKs). Inhibiting JNK and ERK pathways restores sensitivity to dexamethasone-induced apoptosis, offering potential therapeutic strategies.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Pharmacology

Background:

  • Glucocorticoids are key chemotherapeutics for lymphoid malignancies, inducing apoptosis via the glucocorticoid receptor.
  • Mechanisms of glucocorticoid resistance and apoptosis remain incompletely understood.
  • Mitogen-activated protein kinases (MAPKs) modulate cellular responses and can affect glucocorticoid receptor activity.

Purpose of the Study:

  • To investigate how pharmaceutical interventions targeting the MAPK pathway influence glucocorticoid sensitivity in lymphoid cells.
  • To explore mechanisms underlying dexamethasone resistance in human acute lymphoblastic leukemia (CEM) cells.

Main Methods:

  • Utilized sensitive and resistant CEM cell clones.
  • Assessed MAPK pathway activity (JNK, ERK, p38) following dexamethasone treatment.
  • Evaluated effects of MAPK inhibitors, forskolin (cAMP/PKA pathway activator), and rapamycin (mTOR inhibitor) on dexamethasone sensitivity.

Main Results:

  • Resistant CEM cells exhibited high constitutive JNK and induced ERK activity.
  • Inhibition of JNK and ERK, or activation of cAMP/PKA with forskolin, or mTOR inhibition with rapamycin restored dexamethasone sensitivity.
  • These treatments modulated phospho-MAPK levels and increased glucocorticoid receptor phosphorylation at serine 211, enhancing receptor activity.

Conclusions:

  • MAPKs (JNK, ERK) counteract glucocorticoid-dependent apoptosis in lymphoid cells.
  • Inhibiting specific MAPKs restores corticoid sensitivity in resistant cells.
  • Modulation of cellular pathways (cAMP, mTOR) and MAPK activity, alongside increased phospho-serine 211 glucocorticoid receptor, presents therapeutic potential for lymphoid malignancies.

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