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

Oskar W Rokhlin; Natalya V Guseva; Agshin F Taghiyev; Rebecca A Glover; Michael B Cohen

doi:10.4161/cbt.3.8.970

Back

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

Journal article

Open access

Peer reviewed

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

Oskar W Rokhlin, Natalya V Guseva, Agshin F Taghiyev, Rebecca A Glover and Michael B Cohen

Cancer biology & therapy, Vol.3(8), pp.761-768

08/2004

DOI: 10.4161/cbt.3.8.970

PMID: 15197350

Files and links (1)

url

https://doi.org/10.4161/cbt.3.8.970View

Published (Version of record) Open Access

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.

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

Phosphatidylinositol 3-Kinases - antagonists & inhibitors

Prostatic Neoplasms - metabolism

Prostatic Neoplasms - 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

Details

Title: Subtitle: Multiple effects of N-alpha-tosyl-L-phenylalanyl chloromethyl ketone (TPCK) on apoptotic pathways in human prostatic carcinoma cell lines
Creators: Oskar W Rokhlin - University of Iowa
Natalya V Guseva
Agshin F Taghiyev
Rebecca A Glover
Michael B Cohen
Resource Type: Journal article
Publication Details: Cancer biology & therapy, Vol.3(8), pp.761-768
DOI: 10.4161/cbt.3.8.970
PMID: 15197350
ISSN: 1538-4047
eISSN: 1555-8576
Grant note: CA 87717 / NCI NIH HHS
Language: English
Date published: 08/2004
Academic Unit: Pathology; Biology
Record Identifier: 9984646763402771

Metrics

5 Record Views

16 Times Cited - Web of Science

See more details