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Proteasomal regulation of caspase-8 in cancer cell apoptosis

Michael V Fiandalo1, Steven R Schwarze, Natasha Kyprianou

  • 1Department of Molecular and Cellular Biochemistry and the Markey Cancer Center, University of Kentucky College of Medicine, Combs Cancer Research Building, 306, 800 Rose Street, Lexington, KY 40536, USA.

Apoptosis : an International Journal on Programmed Cell Death
|March 5, 2013
PubMed

Insights

Proteasome inhibition reactivates apoptosis in TRAIL-resistant prostate cancer by stabilizing caspase-8. Targeting the E3 ligase involved in caspase-8 polyubiquitination offers a new therapeutic strategy for resistant tumors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Signaling

Background:

  • Proteasome inhibition enhances TRAIL-induced apoptosis in resistant prostate cancer by stabilizing caspase-8.
  • The precise mechanisms of caspase-8 regulation, including its stability, ubiquitination, and trafficking, remain incompletely understood in the context of proteasome inhibition and TRAIL resistance.

Purpose of the Study:

  • To investigate the role of proteasome inhibition in caspase-8 stability, ubiquitination, trafficking, and activation in cancer cells.
  • To explore the therapeutic potential of targeting caspase-8 regulation in TRAIL-resistant cancers.

Main Methods:

  • Utilized caspase-8 deficient neuroblastoma (NB7) cells reconstituted with non-cleavable caspase-8 mutants.
  • Employed GST-TRAIL and proteasome inhibitors for apoptosis induction.
  • Performed subcellular fractionation to analyze caspase-8 activity.
  • Investigated caspase-8 polyubiquitination in LNCaP human prostate cancer cells.

Main Results:

  • Non-cleavable caspase-8 mutants induced apoptosis similarly to wild-type caspase-8 upon proteasome inhibition and GST-TRAIL treatment.
  • Caspase-8 polyubiquitination was observed after TRAIL stimulation and processing in LNCaP cells.
  • Caspase-8 activity was detected in both cytosolic and plasma membrane fractions.

Conclusions:

  • Proteasome inhibition stabilizes caspase-8, reactivating the extrinsic apoptosis pathway in resistant cancer cells.
  • Identifying the E3 ligase responsible for caspase-8 polyubiquitination presents a novel therapeutic target.
  • Combined inhibition of this E3 ligase with TRAIL may restore apoptosis signaling in resistant tumors, holding therapeutic significance.

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