Department of Thoracic Oncology, Hyogo College of Medicine, Nishinomiya, Japan.
J Cell Physiol. 2011 Mar;226(3):762-8. doi: 10.1002/jcp.22397.
Malignant mesothelioma is an aggressive tumor of serosal surfaces, which is refractory to current treatment options. Arsenic trioxide (As2O3) 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 As2O3 inhibited cell viability of a mesothelioma cell line, NCI-H2052. As2O3 induced apoptosis of NCI-H2052 cells, which was accompanied by activation of c-Jun NH2-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, and caspase-3. zVAD-fmk, a broad-spectrum caspase inhibitor, inhibited As2O3-induced apoptosis and activation of caspase-3, but not that of JNK1/2 and ERK1/2. Small interfering RNAs (siRNAs) targeting JNK1/2 suppressed As2O3-induced caspase-3 activation and apoptosis, indicating that JNK1/2 regulate As2O3-induced apoptosis though caspase cascade. Furthermore, JNK1 siRNA abrogated As2O3-induced JNK2 phosphorylation and JNK2 siRNA abrogated As2O3-induced JNK1 phosphorylation, suggesting that JNK1 and JNK2 interact with each other. Moreover, JNK1 siRNA, but not JNK2 siRNA, abrogated As2O3-induced ERK1/2 phosphorylation. JNK2 siRNA together with PD98059, a specific MAPK/ERK kinase inhibitor, suppressed As2O3-induced apoptosis more significantly than JNK2 siRNA alone. These results indicated that As2O3 induces apoptosis of NCI-H2052 cells mainly through JNK1/2 activation, and that ERK1/2 is involved in As2O3-induced apoptosis when JNK1/2 are inactivated.
恶性间皮瘤是一种侵袭性的浆膜表面肿瘤，对目前的治疗选择具有抗性。三氧化二砷 (As2O3) 临床上用于治疗急性早幼粒细胞白血病，也体外抑制肝癌、食管癌和胃癌等几种实体肿瘤的增殖。在这里，我们发现 As2O3 抑制了间皮瘤细胞系 NCI-H2052 的细胞活力。As2O3 诱导 NCI-H2052 细胞凋亡，伴随着 c-Jun NH2-末端激酶 (JNK)1/2、细胞外信号调节激酶 (ERK)1/2 和半胱氨酸天冬氨酸蛋白酶-3 (caspase-3) 的激活。广谱半胱天冬酶抑制剂 zVAD-fmk 抑制了 As2O3 诱导的细胞凋亡和 caspase-3 的激活，但不抑制 JNK1/2 和 ERK1/2 的激活。靶向 JNK1/2 的小干扰 RNA (siRNA) 抑制了 As2O3 诱导的 caspase-3 激活和细胞凋亡，表明 JNK1/2 通过半胱天冬酶级联反应调节 As2O3 诱导的细胞凋亡。此外，JNK1 siRNA 消除了 As2O3 诱导的 JNK2 磷酸化，而 JNK2 siRNA 消除了 As2O3 诱导的 JNK1 磷酸化，表明 JNK1 和 JNK2 相互作用。此外，JNK1 siRNA 而不是 JNK2 siRNA 消除了 As2O3 诱导的 ERK1/2 磷酸化。JNK2 siRNA 与 PD98059（一种特异性 MAPK/ERK 激酶抑制剂）联合使用，比单独使用 JNK2 siRNA 更显著地抑制了 As2O3 诱导的细胞凋亡。这些结果表明，As2O3 主要通过 JNK1/2 的激活诱导 NCI-H2052 细胞凋亡，而当 JNK1/2 失活时，ERK1/2 参与了 As2O3 诱导的细胞凋亡。
