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Apoptosis induction by the glucocorticoid hormone dexamethasone and the calcium-ATPase inhibitor thapsigargin

K S McColl1, H He, H Zhong

  • 1Department of Medicine, Case Western Reserve University/Ireland Cancer Center, Cleveland, OH 44106-4937, USA.

Molecular and Cellular Endocrinology
|August 15, 1998
PubMed

Insights

This study shows that caspases (ICE-like proteases) are essential for apoptosis in mouse lymphoma cells induced by dexamethasone and thapsigargin. Bcl-2 inhibits this caspase activation, revealing a common pathway for diverse death signals.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Apoptosis, or programmed cell death, is crucial for development and tissue homeostasis.
  • Caspases are key executioner proteases in apoptosis, but their precise role in response to diverse death signals requires clarification.
  • The Bcl-2 protein is a known regulator of apoptosis, but its interaction with caspase activation pathways is complex.

Purpose of the Study:

  • To investigate the role of caspases in mediating apoptosis induced by two distinct agents: dexamethasone (DX) and thapsigargin (TG).
  • To determine if these diverse death signals converge on a common caspase-dependent pathway.
  • To examine the influence of Bcl-2 on caspase activation and apoptosis.

Main Methods:

  • WEHI7.2 mouse lymphoma cells were treated with DX or TG.
  • Caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage were assessed.
  • In vitro cleavage of baculovirus p35 was used to assay caspase activity.
  • Cell-permeant caspase inhibitors (Z-VAD-fmk, Z-DEVD-fmk) were used to block apoptosis in vivo.
  • Bcl-2 overexpression was employed to study its regulatory role.

Main Results:

  • Apoptosis induction by DX and TG correlated with caspase-3 activation and PARP cleavage.
  • Bcl-2 overexpression inhibited both caspase activation and PARP cleavage.
  • Cell extracts from treated cells cleaved the p35 substrate, indicating active caspase-like proteases.
  • Caspase inhibitors effectively blocked apoptotic nuclear changes and maintained plasma membrane integrity.
  • Optimal timing for caspase inhibition was crucial, especially for DX-induced apoptosis.

Conclusions:

  • Two distinct apoptosis-inducing signals (dexamethasone and thapsigargin) converge on a common pathway involving caspase activation.
  • This common pathway is regulated by Bcl-2.
  • Caspases are essential executioners of apoptosis in this model, and their inhibition can prevent cell death.
  • The findings highlight the central role of caspases in diverse apoptotic signaling.

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