Increased aquaglyceroporin 9 expression disrupts arsenic resistance in human lung cancer cells.
Resistance to chemotherapy is one of the major problems in treatment responses of lung cancer. This study explored the mechanism underlying the arsenic resistance of lung cancer. Four lung cancer cells with different proliferation activity were characterized for cytotoxicity, arsenic influx/efflux, and arsenic effects on intracellular glutathione and 8-hydroxy-2'-deoxyguanosine (8-OHdG) production. Our data revealed that relative proliferation potency of these cells was H1299>A549>CL3>H1355. Moreover, A549, H1299, and H1355 were markedly resistant to As(2)O(3) with IC50 approximately 100 microM, whereas CL3 was sensitive to As(2)O(3) with IC50 approximately 11.8 microM. After treatment with the respective As(2)O(3) at IC50, arsenic influx/efflux activity in CL3 was comparable to those in the other three arsenic-resistant cells. However, differences in glutathione levels and 8-OHdG production were also detected either before or after arsenic treatment, indicating that a certain degree of variation in anti-oxidative systems and/or 8-OHdG repair activity existed in these cell lines. By transfection of an aquaglyceroporin 9 (AQP9) gene, we showed that increased AQP9 expression significantly enhanced arsenic uptake and disrupted arsenic resistance of A549. The present study strongly suggests that membrane transporters responsible for arsenic uptake, such as AQP9, may play a critical role in development of arsenic resistance in human lung cancer cells.
Miao
Zhi-Feng
ZF
Laboratory of Molecular Toxicology, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.
Chang
Eddy Essen
EE
Tsai
Feng-Yuan
FY
Yeh
Szu-Ching
SC
Wu
Chia-Fang
CF
Wu
Kuen-Yuh
KY
Wang
Chien-Jen
CJ
Tsou
Tsui-Chun
TC
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000378:metabolism / Q000494:pharmacology*
C109669:AQP9 protein, human; D000970:Antineoplastic Agents; D020346:Aquaporins; D001152:Arsenicals; D010087:Oxides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D005978:Glutathione; D000077237:Arsenic Trioxide