Multiple effects of N-alpha-tosyl-L-phenylalanyl chloromethyl ketone (TPCK) on apoptotic pathways in human prostatic carcinoma cell lines.

Abstract

TPCK is widely used as an inhibitor of chymotrypsin-like proteases but has recently been identified as an inhibitor of the PDK1/Akt pathway. In this study, we show that TPCK inhibits TRAIL-induced caspase activity but potentiates wortmannin-dependent caspase activity in prostatic carcinoma cell lines. The inhibitory activity of TPCK was found to be death ligand-specific since TPCK inhibits TRAIL-mediated caspase activity but does not affect Fas-induced caspase activity. Our data also show that impaired TRAIL-DISC formation in the presence of TPCK is responsible for caspase inhibition. Further, TPCK induces p53 expression and inhibits the PDK1/Akt pathway resulting in BAD dephosphorylation, and the release of cytochrome c and Smac/DIABLO from mitochondria. TPCK also selectively decreases the levels of androgen receptor and caspase-2 whereas it does not change the levels of other proteins (caspases-3, -7, -8, -9; heat shock proteins 27, 70, 90). Finally, TPCK-induced degradation of caspase-2 is protected by Bcl-2 overexpression, apparently by an adapter protein since direct interaction between caspase-2 and Bcl-2 was not detected. Together, these features suggest that TPCK could be used as a therapeutic agent for treatment of those tumor cells that are resistant to ligand-induced treatment because of aberrant signaling pathways downstream of the DISC.

• Authors: Oskar W Rokhlin, Natalya V Guseva, Agshin F Taghiyev, Rebecca A Glover, Michael B Cohen
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 3 Issue 8 Pg. 761-8 (Aug 2004) ISSN: 1538-4047 [Print] United States
• PMID: 15197350 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkylating Agents
• Androstadienes
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Death Domain Receptor Signaling Adaptor Proteins
• Membrane Glycoproteins
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Tumor Necrosis Factor
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• Tosylphenylalanyl Chloromethyl Ketone
• Caspases
• Wortmannin

Topics

• Alkylating Agents (pharmacology)
• Androstadienes (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins
• Caspases (metabolism)
• Death Domain Receptor Signaling Adaptor Proteins
• Humans
• Male
• Membrane Glycoproteins (pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Prostatic Neoplasms (metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Tumor Necrosis Factor (metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand
• Tosylphenylalanyl Chloromethyl Ketone (pharmacology)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (pharmacology)
• Wortmannin