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Chemical sensitization and regulation of TRAIL‐induced apoptosis in a panel of B‐lymphocytic leukaemia cell lines
Author(s) -
Kang Jian,
Kisenge Rodrick R.,
Toyoda Hidemi,
Tanaka Shigeki,
Bu Jun,
Azuma Eiichi,
Komada Yoshihiro
Publication year - 2003
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2003.04699.x
Subject(s) - xiap , fadd , apoptosis , caspase 8 , caspase , programmed cell death , caspase 3 , tumor necrosis factor alpha , cycloheximide , cancer research , cell culture , caspase 10 , biology , caspase 9 , microbiology and biotechnology , chemistry , immunology , biochemistry , genetics
Summary. Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) effectively kills tumour cells but not normal cells. We investigated TRAIL sensitivity and the TRAIL‐induced apoptosis signalling pathway in a panel of B‐lymphocytic leukaemia cell lines. Depending upon TRAIL sensitivity, leukaemia cells could be divided into three groups: highly sensitive, moderately sensitive and resistant. TRAIL receptor‐2 (DR5) plays an important role in transducing apoptosis signals. DR5 was internalized into the cytoplasm where it recruited FAS‐associated death domain protein (FADD) under TRAIL stimulation in both sensitive and resistant cells. However, the active form of caspase‐8 was recruited to FADD and only sensitive cells showed increased caspase‐8 activity upon TRAIL stimulation. The caspase‐8 specific inhibitor, Z‐IETD, impaired caspase‐8 activation and completely abrogated TRAIL‐induced apoptosis. These results suggest that TRAIL resistance in B‐lymphocytic leukaemia cells is due to negative regulation at the level of caspase‐8 activation and that caspase‐8 activation is an indispensable process in TRAIL‐induced apoptosis. However, FADD‐like interleukin‐1 β‐converting enzyme inhibitory protein (c‐FLIP L ) was similarly expressed and down‐regulated after TRAIL stimulation in both sensitive and resistant cells. Interestingly, in some cell lines, TRAIL sensitivity and caspase‐8 activity was enhanced or restored with the treatment of cycloheximide (CHX). In addition, X‐linked inhibitor of apoptosis (XIAP) levels decreased significantly and rapidly following treatment with CHX. Down‐regulation of XIAP may be responsible for enhancement or restoration of TRAIL sensitivity after CHX treatment in B‐lymphocytic leukaemia cells.