Treatment of lung cancer cells with cytotoxic levels of sodium selenite: effects on the thioredoxin system.
Selenium at subtoxic doses has been shown to have tumor specific cytotoxic effects. In this work, viability measurements in different lung cancer cell lines showed that selenite was more effective compared to three different conventional cytotoxic drugs. In addition, the cell line most sensitive to selenite toxicity comprised the highest level of thioredoxin reductase 1 (TrxR1). The human selenoenzyme TrxR1 is a central enzyme for cell growth, differentiation, and the protection against oxidative stress. TrxR1, which in several studies has been shown to be up-regulated in various tumor cells, is also a target for many anticancer drugs. In this study, inhibition of TrxR resulted in enhanced selenite cytotoxicity, clearly connecting the thioredoxin system to the toxic effects mediated by selenite. The complex regulation of TrxR1, involving the expression of many different transcript forms of mRNA, was investigated by real-time qPCR in lung cancer cell lines following treatment with toxic doses (2.5-10 microM) of sodium selenite. Selenium treatment resulted in increased expression of almost all TrxR1 mRNA variants with increasing concentrations of selenite. On the contrary, the TrxR protein level and activity, increased at low to moderate doses followed by a decrease at higher doses, indicating impairment of protein synthesis by selenite.
Selenius
Markus
M
Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology F46, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
Fernandes
Aristi Potamitou
AP
Brodin
Ola
O
Björnstedt
Mikael
M
Rundlöf
Anna-Klara
AK
D000970:Antineoplastic Agents / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018038:Sodium Selenite / Q000633:toxicity*; D054481:Thioredoxin Reductase 1 / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013879:Thioredoxins; D054481:Thioredoxin Reductase 1; D018038:Sodium Selenite