Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53.
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.
Herrmann
J L
JL
The Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Briones
F
F
Brisbay
S
S
Logothetis
C J
CJ
McDonnell
T J
TJ
D000447:Aldehydes / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism; D051176:beta Catenin
D000447:Aldehydes; D051017:Apoptosis Regulatory Proteins; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C116501:acetyl-leucinal-leucinal-normethional; C116500:acetyl-leucinal-nor-leucinal; D051176:beta Catenin; C101296:prostate apoptosis response-4 protein; D000072000:NF-KappaB Inhibitor alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D007930:Leucine