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Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy

E Laane1, K Pokrovskaja Tamm, E Buentke

  • 1Department of Oncology and Pathology, Cancer Centre Karolinska R8:03, Karolinska Institutet and Karolinska University Hospital, Stockholm S-171 76, Sweden.

Cell Death and Differentiation
|April 25, 2009
PubMed

Insights

Dexamethasone induces autophagy before apoptosis in acute lymphoblastic leukemia cells. Autophagy inhibition blocks cell death, revealing its crucial role in glucocorticoid cancer therapy.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background:

  • Glucocorticoids are standard treatments for lymphoid malignancies, primarily acting via apoptosis.
  • Autophagy, a cell death pathway, is increasingly recognized in anticancer drug responses, but its role alongside apoptosis is debated.
  • The precise interplay between autophagy and apoptosis in glucocorticoid treatment requires elucidation.

Purpose of the Study:

  • To investigate the role and mechanism of autophagy in dexamethasone-induced cell death in acute lymphoblastic leukemia (ALL).
  • To determine the relationship between autophagy, apoptosis, and the promyelocytic leukemia protein (PML) pathway in ALL.
  • To identify potential therapeutic targets for enhancing glucocorticoid efficacy in lymphoid malignancies.

Main Methods:

  • Utilized siRNA to inhibit Beclin 1 expression, a key autophagy regulator.
  • Examined dexamethasone-induced changes in autophagy and apoptosis markers in ALL cells.
  • Investigated the interaction between PML, Akt (protein kinase B), and their dephosphorylation status.
  • Assessed dexamethasone sensitivity in PML knockout thymocytes.

Main Results:

  • Dexamethasone treatment initiated autophagy preceding apoptosis in ALL cells.
  • Inhibition of autophagy via Beclin 1 knockdown abrogated dexamethasone-induced apoptosis.
  • Dexamethasone upregulated PML, leading to PML-Akt complex formation and Akt dephosphorylation, which were essential for both autophagy and apoptosis.
  • PML-deficient cells exhibited resistance to dexamethasone, and increased PML levels correlated with drug-induced cell death.

Conclusions:

  • Autophagy plays a critical, pro-death role upstream of apoptosis in dexamethasone-treated ALL cells.
  • The PML-Akt signaling axis is a key mediator of dexamethasone-induced autophagy and apoptosis.
  • Targeting the PML pathway and modulating autophagy may offer novel strategies for improving lymphoid malignancy treatment.

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