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Inflammasome-mediated glucocorticoid resistance: The receptor rheostat

Steven W Paugh1, Erik J Bonten1, William E Evans1

  • 1Hematological Malignancies Program, and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital , Memphis, TN, USA.

Molecular & Cellular Oncology
|June 17, 2016
PubMed

Insights

Decreased methylation of caspase 1 (CASP1) and NLRP3 inflammasome genes in acute lymphoblastic leukemia cells promotes glucocorticoid resistance by activating CASP1 and cleaving the glucocorticoid receptor.

Area of Science:

  • Molecular Biology
  • Immunology
  • Oncology

Background:

  • Glucocorticoids are crucial in treating acute lymphoblastic leukemia (ALL).
  • De novo glucocorticoid resistance remains a significant challenge in ALL therapy.
  • Understanding resistance mechanisms is vital for improving treatment outcomes.

Purpose of the Study:

  • To elucidate a novel molecular mechanism underlying de novo glucocorticoid resistance in primary ALL cells.
  • To investigate the roles of caspase 1 (CASP1) and NLRP3 inflammasome in glucocorticoid resistance.

Main Methods:

  • Analysis of promoter methylation in primary ALL cells.
  • Measurement of gene transcription for CASP1 and NLRP3.
  • Assessment of inflammasome activation and its downstream effects.
  • Recapitulation of findings in relevant model systems.

Main Results:

  • Primary ALL cells with de novo glucocorticoid resistance showed decreased promoter methylation of CASP1 and NLRP3.
  • This epigenetic alteration led to increased CASP1 and NLRP3 transcription.
  • Constitutive activation of the NALP3 inflammasome was observed.
  • Caspase 1-mediated cleavage of the glucocorticoid receptor was identified as a key event.

Conclusions:

  • Epigenetic dysregulation of CASP1 and NLRP3 contributes to glucocorticoid resistance in ALL.
  • NLRP3 inflammasome activation and subsequent caspase 1 activity represent a novel mechanism of resistance.
  • Targeting this pathway may offer new therapeutic strategies for overcoming glucocorticoid resistance in ALL.
Keywords:
CASP1NALP3NR3C1glucocorticoidsinflammasome

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