Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53

Oncogene. 1998 Dec 3;17(22):2889-99. doi: 10.1038/sj.onc.1202221.

Abstract

The ATP/ubiquitin-dependent 26S proteasome is a central regulator of cell cycle progression and stress responses. While investigating the application of peptide aldehyde proteasome inhibitors to block signal-induced IkappaBalpha degradation in human LNCaP prostate carcinoma cells, we observed that persistent inhibition of proteasomal activity signals a potent cell death program. Biochemically, this program included substantial upregulation of PAR-4 (prostate apoptosis response-4), a putative pro-apoptotic effector protein and stabilization of c-jun protein, a potent pro-death effector in certain cells. We also observed modest downregulation of bcl-XL, a pro-survival effector protein. However, in contrast to some recent reports stable, high level, expression of functional bcl-2 protein in prostate carcinoma cells failed to signal protection against cell death induction by proteasome inhibitors. Also in disagreement to a recent report, no evidence was found for activation of the JNK stress kinase pathway. A role for p53, a protein regulated by the proteasome pathway, was ruled out, since comparable cell death induction by proteasome inhibitors occurred in PC-3 cells that do not express functional p53 protein. These data signify that the ubiquitin/proteasome pathway represents a potential therapeutic target for prostate cancers irrespective of bcl-2 expression or p53 mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / pharmacology
  • Aldehydes / therapeutic use
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carrier Proteins / metabolism
  • Cell Death / drug effects*
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • I-kappa B Proteins*
  • Intracellular Signaling Peptides and Proteins*
  • JNK Mitogen-Activated Protein Kinases
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Male
  • Mitogen-Activated Protein Kinases*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Peptide Hydrolases / metabolism*
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / physiopathology*
  • Proteasome Endopeptidase Complex*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Signal Transduction / drug effects
  • Trans-Activators*
  • Transcription Factor RelA
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitins / metabolism
  • beta Catenin

Substances

  • Aldehydes
  • Apoptosis Regulatory Proteins
  • CTNNB1 protein, human
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-jun
  • Trans-Activators
  • Transcription Factor RelA
  • Tumor Suppressor Protein p53
  • Ubiquitins
  • acetyl-leucinal-leucinal-normethional
  • acetyl-leucinal-nor-leucinal
  • beta Catenin
  • prostate apoptosis response-4 protein
  • NF-KappaB Inhibitor alpha
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Leucine