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J. Biol. Chem., Vol. 281, Issue 19, 13005-13008, May 12, 2006

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Thioredoxin Reductase 1 Deficiency Reverses Tumor Phenotype and Tumorigenicity of Lung Carcinoma Cells^*

Min-Hyuk Yoo, Xue-Ming Xu, Bradley A. Carlson, Vadim N. Gladyshev, and Dolph L. Hatfield¹

From the Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892 and the Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588

Dietary selenium has potent cancer prevention activity. Both low molecular weight selenocompounds and selenoproteins are implicated in this effect. Thioredoxin reductase 1 (TR1) is one of the major antioxidant and redox regulators in mammals that supports p53 function and other tumor suppressor activities. However, this selenium-containing oxidoreductase is also overexpressed in many malignant cells and has been proposed as a target for cancer therapy. To further assess the role of TR1 in the malignancy process, we used RNA interference technology to decrease its expression in mouse lung carcinoma (LLC1) cells. Stable transfection of LLC1 cells with a small interfering RNA construct that specifically targets TR1 removal manifested a reversal in the morphology and anchorage-independent growth properties of these cancer cells that made them similar to those of normal cells. The expression of at least two cancer-related protein mRNAs, Hgf and Opn1, were reduced dramatically in the TR1 knockdown cells. Mice injected with the TR1 knockdown showed a dramatic reduction in tumor progression and metastasis compared with those mice injected with the corresponding control vector. In addition, tumors that arose from injected TR1 knockdown cells lost the targeting construct, suggesting that TR1 is essential for tumor growth in mice. These observations provide direct evidence that the reduction of TR1 levels in malignant cells is antitumorigenic and suggest that the enzyme is a prime target for cancer therapy.

Received for publication, January 27, 2006 , and in revised form, March 20, 2006.

^* This research was supported by the Intramural Reseach Program of the National Institutes of Health, NCI, Center for Cancer Research and by Grants GM065204 and CA080946 (to V. N. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data, Figs. 1 and 2, and Ref. S1.

¹ To whom correspondence should be addressed: MBSS, LCP, NCI, National Institutes of Health, Bldg. 37, Rm. 6032, Bethesda, MD 20892. Tel.: 301-496-2797; Fax: 301-435-4957; E-mail: hatfield{at}mail.nih.gov.

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