JWA sensitizes P-glycoprotein-mediated drug-resistant choriocarcinoma cells to etoposide via JNK and mitochondrial-associated signal pathway.
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.
Zhang
Yan
Y
Department of Molecular Cell Biology and Genetics, Cancer Centre, Nanjing Medical University, Nanjing, People's Republic of China.
Zhou
Jinhong
J
Xu
Wenxia
W
Li
Aiping
A
Zhou
Jianwei
J
Xu
Shan
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000188:drug therapy* / Q000473:pathology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D006360:Heat-Shock Proteins / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D048670:MAP Kinase Kinase 4 / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D026901:Membrane Transport Proteins; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
C484566:ARL6IP5 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D005047:Etoposide; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4