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Protease inhibitors differentially regulate tumor necrosis factor- induced
apoptosis, nuclear factor-kappa B activation, cytotoxicity, and
differentiation
M Higuchi, S Singh, H Chan and BB Aggarwal
Department of Molecular Oncology, University of Texas M.D. Anderson Cancer
Center, Houston 77030, USA.
We investigated the effect of various protease inhibitors on several tumor
necrosis factor (TNF)-mediated cellular responses. Treatment of a human
myelogenous leukemia cell line, ML-1a, with TNF in the presence of
cycloheximide triggers endonucleolytic activity and apoptotic cell death
within 90 minutes. The general serine protease inhibitor diisopropyl
fluorophosphate (DFP) and the chymotrypsin-like protease inhibitor
N-tosyl-L-lysyl chloromethyl ketone (TPCK) completely abrogated TNF-induced
DNA fragmentation and the formation of apoptotic bodies. However, 13 other
protease inhibitors, including serine protease inhibitors, did not. The
addition of TPCK to cells 30 minutes after TNF treatment completely
inhibited the cytokine action, indicating that TPCK-sensitive proteases are
not involved in the early stages of signal transduction. TNF is cytotoxic
and induces differentiation in ML-1a cells after a 3-day incubation. TPCK
had no effect on the TNF-induced cytotoxicity and differentiation,
indicating that TPCK-sensitive proteases are specific for DNA
fragmentation. TPCK also blocked TNF-induced activation of nuclear factor
(NF)-kappa B. The dose-response and the time-course of the inhibitor,
however, indicated that the site of action of TPCK for NF-kappa B
activation and for DNA fragmentation are quite distinct. Therefore, we
conclude that TNF activates two distinct TPCK-sensitive pathways, one
leading to apoptosis and the other to NF-kappa B activation.
Volume 86,
Issue 6,
pp. 2248-2256,
09/15/1995
Copyright © 1995 by The American Society of Hematology
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