Zhang Yan, Zhou Jinhong, Xu Wenxia, Li Aiping, Zhou Jianwei, Xu Shan
Department of Molecular Cell Biology and Genetics, Cancer Centre, Nanjing Medical University, Nanjing, People's Republic of China.
J Toxicol Environ Health A. 2009;72(11-12):774-81. doi: 10.1080/15287390902841649.
A major obstacle in cancer chemotherapy is the phenomenon of multidrug resistance (MDR), increased P-glycoprotein expression, and abnormal apoptotic processes that may contribute to MDR. Our previous studies demonstrated that JWA is a pro-apoptotic molecule and required for arsenic trioxide and all-trans-retinoic acid-induced cancer cell apoptosis. In this study, the role of JWA in mediating MDR during treatment of choriocarcinoma cells was examined. Data showed that JWA expression was reduced significantly by etoposide (VP16) in JAR MDR cells (JAR/VP16) compared to parent JAR cells. VP16-induced apoptosis in JAR cells was dependent upon the presence of JWA. Knockdown of JWA attenuated VP16-induced apoptosis, and was accompanied by significantly reduced caspase-9 activity and inhibition of JNK phosphorylation. Loss of mitochondrial transmembrane potential induced by VP16 was accompanied by higher JWA expression. JWA was also involved in downregulation of P-glycoprotein through JNK signal pathway. These results suggest that JWA may play an important role in the therapeutic responses to chemotherapeutic agents used to treat choriocarcinoma.
癌症化疗中的一个主要障碍是多药耐药（MDR）现象、P-糖蛋白表达增加以及可能导致MDR的异常凋亡过程。我们之前的研究表明，JWA是一种促凋亡分子，是三氧化二砷和全反式维甲酸诱导癌细胞凋亡所必需的。在本研究中，我们检测了JWA在绒癌细胞治疗过程中介导MDR的作用。数据显示，与亲代JAR细胞相比，依托泊苷（VP16）显著降低了JAR MDR细胞（JAR/VP16）中JWA的表达。VP16诱导JAR细胞凋亡依赖于JWA的存在。敲低JWA可减弱VP16诱导的凋亡，并伴有caspase-9活性显著降低和JNK磷酸化受抑制。VP16诱导的线粒体跨膜电位丧失伴随着更高的JWA表达。JWA还通过JNK信号通路参与P-糖蛋白的下调。这些结果表明，JWA可能在用于治疗绒癌的化疗药物的治疗反应中起重要作用。
