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J. Biol. Chem., Vol. 283, Issue 6, 3418-3423, February 8, 2008

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Aldo-keto Reductase Family 1 B10 Affects Fatty Acid Synthesis by Regulating the Stability of Acetyl-CoA Carboxylase- in Breast Cancer Cells^*

Jun Ma, Ruilan Yan, Xuyu Zu, Ji-Ming Cheng^¶, Krishna Rao^¶, Duan-Fang Liao, and Deliang Cao¹

From the Department of Medical Microbiology, Immunology, and Cell Biology, SimmonsCooper Cancer Institute, and ^¶Division of Hematology/Oncology, Internal Medicine, Southern Illinois University School of Medicine, Springfield, Illinois 62702 and Division of Pharmacoproteomics, Institute of Pharmacy and Pharmacology, Nanhua University School of Life Science and Technology, 28 Changshengxi Road, Hengyang, Hunan 421001, China

Recent studies have demonstrated that aldo-keto reductase family 1 B10 (AKR1B10), a novel protein overexpressed in human hepatocellular carcinoma and non-small cell lung carcinoma, may facilitate cancer cell growth by detoxifying intracellular reactive carbonyls. This study presents a novel function of AKR1B10 in tumorigenic mammary epithelial cells (RAO-3), regulating fatty acid synthesis. In RAO-3 cells, Sephacryl-S 300 gel filtration and DEAE-Sepharose ion exchange chromatography demonstrated that AKR1B10 exists in two distinct forms, monomers (40 kDa) bound to DEAE-Sepharose column and protein complexes (300 kDa) remaining in flow-through. Co-immunoprecipitation with AKR1B10 antibody and protein mass spectrometry analysis identified that AKR1B10 associates with acetyl-CoA carboxylase- (ACCA), a rate-limiting enzyme of de novo fatty acid synthesis. This association between AKR1B10 and ACCA proteins was further confirmed by co-immunoprecipitation with ACCA antibody and pulldown assays with recombinant AKR1B10 protein. Intracellular fluorescent studies showed that AKR1B10 and ACCA proteins co-localize in the cytoplasm of RAO-3 cells. More interestingly, small interfering RNA-mediated AKR1B10 knock down increased ACCA degradation through ubiquitination-proteasome pathway and resulted in >50% decrease of fatty acid synthesis in RAO-3 cells. These data suggest that AKR1B10 is a novel regulator of the biosynthesis of fatty acid, an essential component of the cell membrane, in breast cancer cells.

Received for publication, September 12, 2007 , and in revised form, November 30, 2007.

^* This work was supported in part by American Cancer Society Grant RSG-04-031-01-CCE), SimmonsCooper Cancer Institute Award and Central Research Committee. Near-Miss Award, Southern Illinois University School of Medicine, and NCI, National Institutes of Health Grant CA122327. 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 Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Medical Microbiology, Immunology, and Cell Biology, SimmonsCooper Cancer Inst., Southern Illinois University School of Medicine. 913 N. Rutledge St., Springfield, IL 62702. Tel.: 217-545-9703; Fax: 217-545-9718; E-mail: dcao{at}siumed.edu.

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