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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

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Dexamethasone-induced apoptosis and up-regulation of Bim is dependent on glycogen synthase kinase-3

Ulla Nuutinen1, Antti Ropponen, Sanna Suoranta

  • 1Department of Clinical Microbiology, Institute of Clinical Medicine, University of Kuopio, Yliopistonranta 1 C, 70210 Kuopio, Finland. ulla-maija.nuutinen@uku.fi

Leukemia Research
|June 30, 2009
PubMed

Insights

Dexamethasone-induced apoptosis in lymphoid malignancies relies on mitochondria and caspase-9. Glycogen synthase kinase 3 (GSK3) inhibition blocks this process by controlling Bim, a key protein in apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Glucocorticoids, like dexamethasone (Dex), are standard treatments for lymphoid malignancies.
  • Understanding the precise mechanisms of glucocorticoid-induced apoptosis is crucial for optimizing cancer therapy.

Purpose of the Study:

  • To elucidate the role of mitochondria and specific signaling pathways in dexamethasone-induced apoptosis of lymphoid cells.
  • To investigate the involvement of caspase-9 and glycogen synthase kinase 3 (GSK3) in this apoptotic process.

Main Methods:

  • Overexpression of Bcl-X(L) to assess mitochondrial dependence.
  • Use of dominant-negative (DN) caspase-9 to evaluate caspase-9's role.
  • Inhibition of GSK3 to determine its contribution to apoptosis.

Main Results:

  • Dexamethasone-induced apoptosis was dependent on mitochondria, as shown by Bcl-X(L) overexpression preventing apoptotic changes.
  • DN caspase-9 inhibited Dex-induced apoptosis and mitochondrial membrane potential loss, indicating caspase-9 controls mitochondrial events.
  • GSK3 inhibition attenuated Dex-induced Bim up-regulation, mitochondrial dysfunction, cytochrome c release, and DNA fragmentation.

Conclusions:

  • Mitochondria and caspase-9 are critical effectors of dexamethasone-induced apoptosis in lymphoid malignancies.
  • Glycogen synthase kinase 3 (GSK3) plays a significant role in this process by regulating Bim expression.

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