| Title | High levels of thioredoxin reductase 1 modulate drug-specific cytotoxic efficacy. | | Author(s) | Eriksson SE, Prast-Nielsen S, Flaberg E, Szekely L, Arnér ES | | Institution | Division of Biochemistry, Department of Medical Biochemistry and Biophysics. | | Source | Free Radic Biol Med 2009 Sep 17. | | Abstract | The selenoprotein thioredoxin reductase 1 (TrxR1) is currently recognized as a plausible anticancer drug target. Here we therefore analyzed the effects of TrxR1 targeting in human A549 lung adenocarcinoma cells, having very high basal TrxR1 expression. We determined the total cellular TrxR activity to 271.4 +/- 39.5 nmol x min(-1) per mg total protein, which by far exceeded the total thioredoxin (Trx) activity (39.2 +/- 3.5 nmol x min(-1) per mg total protein). Knocking down TrxR1 by approx. 90% using siRNA gave only a slight effect on cell growth, irrespective of concurrent glutathione depletion (>/= 98% decrease), and no increase in cell death or distorted cell cycle phase distributions. This apparent lack of phenotype was likely explained by maintained Trx functions with the remaining TrxR1 activity. TrxR1 knockdown nonetheless yielded drug-specific modulation of cytotoxic efficacy in response to different chemotherapeutic agents. No changes in response upon exposure to auranofin or juglone were seen after TrxR1 knockdown, whereas sensitivity to 1-chloro-2,4-dinitrobenzene or menadione became markedly increased. In contrast, a virtually complete resistance towards cisplatin using concentrations up to 20 microM appeared upon TrxR1 knockdown. The results suggest that high overexpression of TrxR has an impact not necessarily linked to Trx function that nonetheless modulates drug-specific cytotoxic responses. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19766715 |
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