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TSA-induced cell death in prostate cancer cell lines is caspase-2 dependent and involves the PIDDosome

Agshin F Taghiyev1, Natalya V Guseva, Rebecca A Glover

  • 1Department of Pathology, The University of Iowa, Iowa City, Iowa 52242-1087, USA.

Cancer Biology & Therapy
|November 18, 2006
PubMed

Insights

Trichostatin A (TSA) triggers apoptosis in prostate cancer cells by activating caspase-2. This initiates the mitochondrial pathway, leading to cell death and involving PIDDosome formation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Histone deacetylase inhibitors like Trichostatin A (TSA) induce apoptosis in cancer cells.
  • TSA activates caspases and triggers the mitochondrial pathway in prostate cancer cells.

Purpose of the Study:

  • To elucidate the upstream mechanisms by which TSA initiates the caspase cascade in prostate cancer cells.
  • To determine the role of caspase-2 in TSA-induced apoptosis.

Main Methods:

  • Utilized siRNA and dominant-negative caspase-2 (caspase-2dn) to inhibit caspase-2 activity.
  • Assessed caspase activity, cytochrome c release, and cell viability post-TSA treatment.
  • Performed coimmunoprecipitation to identify caspase-2 interacting proteins.

Main Results:

  • Inhibition of caspase-2 significantly reduced TSA-induced caspase activity and cell death.
  • Caspase-2 was found to act upstream of caspase-8 and -9, mediating mitochondrial cytochrome c release.
  • Caspase-2 formed protein complexes with RADD/RAIDD and PIDD, indicating PIDDosome involvement.

Conclusions:

  • Caspase-2 is a critical initiator of the caspase cascade in TSA-treated prostate cancer cells.
  • The findings highlight the role of the PIDDosome complex in TSA-induced apoptosis via the mitochondrial pathway.

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