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Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca 2+ ‐dependent production of superoxide
Author(s) -
Iwama Kazuki,
Nakajo Shigeo,
Aiuchi Toshihiro,
Nakaya Kazuyasu
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1220
Subject(s) - p38 mitogen activated protein kinases , apoptosis , u937 cell , arsenic trioxide , microbiology and biotechnology , programmed cell death , dna fragmentation , cytochrome c , chemistry , biology , kinase , mapk/erk pathway , biochemistry
The mechanism of the induction of apoptosis by arsenic trioxide (As 2 O 3 ), which was demonstrated recently to be an effective inducer of apoptosis in patients with leukemia, was examined in detail in human leukemia U937 cells. Upon treatment of U937 cells with 50 μM of As 2 O 3 , complete inactivation of the kinases ERK1 and ERK2 was detected within 30 min. p38 was activated within 3 hr, and the maximum activity was detected at 6 hr, when DNA fragmentation remained undetectable. Experiments with transfected cells that expressed constitutively activated MEK1 and a specific inhibitor of p38 also suggested that inactivation of ERKs and activation of p38 might be associated with the induction of apoptosis by As 2 O 3 . In contrast to the inactivation of ERKs and the activation of p38, activation of JNK by As 2 O 3 appeared to protect cells against the induction of apoptosis. Treatment of U937 cells with As 2 O 3 also caused the Ca 2+ ‐dependent production of superoxide and intracellular acidification and a decrease in the mitochondrial membrane potential at the early stages of induction of apoptosis by As 2 O 3 . These changes preceded the release of cytochrome c from mitochondria and the activation of caspase‐3. It should be possible to exploit the unusual characteristics of the mechanism of induction of apoptosis by As 2 O 3 in U937 cells by making use of synergistic effects of this compound with other inducers of apoptosis. © 2001 Wiley‐Liss, Inc.