Department of Cellular Immunology, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PR China.
J Cell Biochem. 2010 Apr 15;109(6):1264-73. doi: 10.1002/jcb.22509.
Arsenite (As(III)), an effective chemotherapeutic agent for the acute promyelocytic leukemia (APL) and multiple myeloma (MM), might be also a promise for the therapy of other cancers, including the solid tumors. However, the molecular bases of arsenite-induced cytotoxicity in the tumor cells have not been fully defined. In this study, we have disclosed that arsenite effectively induces the apoptotic response in the HepG2 human hepatoma cells by triggering GADD45alpha induction and the subsequent activation of JNKs/AP-1 cell death pathway. However, signaling events relating to GADD45alpha/JNKs/AP-1 pathway activation have not been observed in HL7702 human diploid hepatic cells under the same arsenite exposure condition. Our results thus have illustrated the selective pro-apoptotic role of arsenite in the hepatoma cells by activating GADD45alpha-dependent cell death pathway whereas with little effect on the normal hepatic cells. The approaches to up-regulate GADD45alpha levels might be helpful in improving the chemotherapeutic action of arsenite on certain solid tumors including hepatoma.
亚砷酸盐（As(III)）是治疗急性早幼粒细胞白血病（APL）和多发性骨髓瘤（MM）的有效化疗药物，也可能是治疗其他癌症（包括实体瘤）的一种有希望的方法。然而，亚砷酸盐在肿瘤细胞中诱导细胞毒性的分子基础尚未完全确定。在这项研究中，我们揭示了亚砷酸盐通过触发 GADD45alpha 诱导和随后激活 JNKs/AP-1 细胞死亡途径，有效地诱导 HepG2 人肝癌细胞的凋亡反应。然而，在相同的亚砷酸盐暴露条件下，HL7702 人二倍体肝细胞中没有观察到与 GADD45alpha/JNKs/AP-1 途径激活相关的信号事件。我们的结果表明，亚砷酸盐通过激活 GADD45alpha 依赖性细胞死亡途径在肝癌细胞中具有选择性的促凋亡作用，而对正常肝细胞几乎没有影响。上调 GADD45alpha 水平的方法可能有助于提高亚砷酸盐对某些实体瘤（包括肝癌）的化疗作用。
