Enhancing effect of connexin 32 gene on vinorelbine-induced cytotoxicity in A549 lung adenocarcinoma cells.
OBJECTIVE
Connexin (Cx) genes exert negative growth effects on tumor cells with certain cell specificity, and tumor-suppressive effects of the Cx genes contribute to enhancement of chemotherapeutical agents-induced cytotoxicity in some cancer cells. Since we and others have been reported that Cx32 acts as a tumor suppressor gene in lung adenocarcinomas, this study was undertaken to estimate if the combination of Cx32-dependent tumor-suppressive effect and vinorelbine (VBN), a chemotherapeutic agent which has been utilized for clinical lung adenocarcinoma treatment, could be effective in enhancing the sensitivity of the lung cancer to VBN treatment.


METHODS
We established the A549 cells (a human lung adenocarcinoma cell line) which had stable expression of Cx32 and estimated effect of Cx32 on VBN-induced cytotoxicity in the established cells.


RESULTS
Cx32 expression in A549 cells significantly potentiated VBN-induced cytotoxicity on the cells due to enhancement of apoptosis induction. The enhancing cytotoxicity in A549 cells by Cx32 mainly depended on a decrease in expression of multi-drug resistance-1 (MDR-1) gene responsible for reduction of VBN accumulation into the cells. We also observed that silencing of Cx32 by siRNA treatment elevated the expression level of MDR-1 mRNA in A549 cells and that inhibition of MDR-1 gene product-dependent function enhanced VBN-induced cytotoxicity in the cells.


CONCLUSIONS
These results suggest that Cx32 contributes to the enhancement of VBN-induced cytotoxicity in A549 cells via the reduction of MDR-1 expression.
Sato
Hiromi
H
Project for Complementary Factors, National Institute of Health and Nutrition, 1-23-1 Toyama, Tokyo 162-8636, Japan.
Fukumoto
Keiko
K
Hada
Sachio
S
Hagiwara
Hiromi
H
Fujimoto
Eriko
E
Negishi
Etsuko
E
Ueno
Koichi
K
Yano
Tomohiro
T
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017630:Connexins / Q000187:drug effects / Q000235:genetics*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D004273:DNA, Neoplasm; D006034:Glycyrrhetinic Acid; D012333:RNA, Messenger; D000097002:Gap Junction beta-1 Protein