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J. Biol. Chem., Vol. 279, Issue 42, 43522-43529, October 15, 2004

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Identification of a Novel Putative Non-selenocysteine Containing Phospholipid Hydroperoxide Glutathione Peroxidase (NPGPx) Essential for Alleviating Oxidative Stress Generated from Polyunsaturated Fatty Acids in Breast Cancer Cells^*

Ahmad Utomo, Xianzhi Jiang, Saori Furuta¶, Jeanho Yun, David S. Levin||, Yi-Chun J. Wang||, Kartiki V. Desai**, Jeffrey E. Green**, Phang-Lang Chen, and Wen-Hwa Lee¶

From the ^¶Department of Biological Chemistry, School of Medicine, University of California, Irvine, California 92697, the Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245, ^||GeneTex Inc., San Antonio, Texas 78245, and the ^**Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892

A dramatic reduction in the expression of a novel phospholipid hydroperoxide glutathione peroxidase (PHGPx), which incorporates cysteine instead of selenocysteine in the conserved catalytic motif was observed in a microarray analysis using cDNAs amplified from mRNA of Brca1-null mouse embryonic fibroblasts. This non-selenocysteine PHGPx named NPGPx is a cytoplasmic protein with molecular mass of 22 kDa and has little detectable glutathione peroxidase activity in vitro. Ectopic expression of NPGPx in Brca1-null cells that were sensitive to oxidative stress induced by hydrogen peroxide conferred a similar resistance level to that of the wild-type cells, suggesting the importance of this protein in reducing oxidative stress. Expression of NPGPx was found in many tissues, including developing mammary gland. However, the majority of breast cancer cell lines studied (11 of 12) expressed very low or undetectable levels of NPGPx irrespective of BRCA1 status. Re-expression of NPGPx in breast cancer lines, MCF-7 and HCC1937, which have very little or no endogenous NPGPx, induced resistance to eicosapentaenoic acid (an omega-3 type of polyunsaturated fatty acid)-mediated cell death. Conversely, inhibition of the expression of NPGPx by the specific small interfering RNA in HS578T breast cancer cells that originally express substantial amounts of endogenous NPGPx increased their sensitivity to eicosapentaenoic acid-mediated cell death. Thus, NPGPx plays an essential role in breast cancer cells in alleviating oxidative stress generated from polyunsaturated fatty acid metabolism.

Received for publication, June 25, 2004 , and in revised form, July 26, 2004.

^* This work was supported by National Institutes of Health Grants CA94170 and CA81020 (to W.-H. L.) and Department of Defense pre-doctoral training Grant DAMD 17-99-1-9402 (to A. U. and X. J.). 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.

These authors contributed equally to the results of this work.

To whom correspondence should be addressed. Tel.: 949-824-4492; Fax: 949-824-9767; E-mail: whlee{at}uci.edu.

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