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Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells
Author(s) -
Eguchi Ryoji,
Fujimori Yoshihiro,
Takeda Hiromi,
Tabata Chiharu,
Ohta Toshiro,
Kuribayashi Kouzo,
Fukuoka Kazuya,
Nakano Takashi
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22397
Subject(s) - arsenic trioxide , mapk/erk pathway , apoptosis , kinase , small interfering rna , cancer research , chemistry , phosphorylation , microbiology and biotechnology , caspase , transfection , biology , programmed cell death , biochemistry , gene
Abstract Malignant mesothelioma is an aggressive tumor of serosal surfaces, which is refractory to current treatment options. Arsenic trioxide (As 2 O 3 ) is used clinically to treat acute promyelocytic leukemia, and also to inhibit proliferation of several solid tumors including hepatoma, esophageal, and gastric cancer in vitro. Here we found that As 2 O 3 inhibited cell viability of a mesothelioma cell line, NCI‐H2052. As 2 O 3 induced apoptosis of NCI‐H2052 cells, which was accompanied by activation of c‐Jun NH 2 ‐terminal kinase (JNK)1/2, extracellular signal‐regulated kinase (ERK)1/2, and caspase‐3. zVAD‐fmk, a broad‐spectrum caspase inhibitor, inhibited As 2 O 3 ‐induced apoptosis and activation of caspase‐3, but not that of JNK1/2 and ERK1/2. Small interfering RNAs (siRNAs) targeting JNK1/2 suppressed As 2 O 3 ‐induced caspase‐3 activation and apoptosis, indicating that JNK1/2 regulate As 2 O 3 ‐induced apoptosis though caspase cascade. Furthermore, JNK1 siRNA abrogated As 2 O 3 ‐induced JNK2 phosphorylation and JNK2 siRNA abrogated As 2 O 3 ‐induced JNK1 phosphorylation, suggesting that JNK1 and JNK2 interact with each other. Moreover, JNK1 siRNA, but not JNK2 siRNA, abrogated As 2 O 3 ‐induced ERK1/2 phosphorylation. JNK2 siRNA together with PD98059, a specific MAPK/ERK kinase inhibitor, suppressed As 2 O 3 ‐induced apoptosis more significantly than JNK2 siRNA alone. These results indicated that As 2 O 3 induces apoptosis of NCI‐H2052 cells mainly through JNK1/2 activation, and that ERK1/2 is involved in As 2 O 3 ‐induced apoptosis when JNK1/2 are inactivated. J. Cell. Physiol. 226: 762–768, 2011. © 2010 Wiley‐Liss, Inc.