Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells

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.