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.