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

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-α (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. 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-α (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. Aldo-keto reductase family 1 B10 (AKR1B10, 2The abbreviations used are: AKR1B10aldo-keto reductase family 1 B10ACCAacetyl-CoA carboxylase-αEGFPenhanced green fluorescent proteinHMEChuman mammary epithelial cellsiRNAsmall-interfering RNANi-NTAnickel-nitrilotriacetic acid. also designated aldose reductase-like-1, ARL-1) is a novel protein identified from human hepatocellular carcinoma (1Cao D. Fan S.T. Chung S.S. J. Biol. Chem. 1998; 273: 11429-11435Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). This protein belongs to the aldo-keto reductase superfamily, a group of proteins implicated in intracellular detoxification, cell carcinogenesis, and cancer therapeutics (2Jin J. Krishack P.A. Cao D. Front Biosci. 2006; 11: 2767-2773Crossref PubMed Scopus (34) Google Scholar, 3Hyndman D. Bauman D.R. Heredia V.V. Penning T.M. Chem. Biol. Interact. 2003; 143–144: 621-631Crossref PubMed Scopus (265) Google Scholar, 4Crosas B. Hyndman D.J. Gallego O. Martras S. Pares X. Flynn T.G. Farres J. Biochem. J. 2003; 373: 973-979Crossref PubMed Google Scholar, 5Lee K.W. Ko B.C. Jiang Z. Cao D. Chung S.S. Anti-Cancer Drugs. 2001; 12: 129-132Crossref PubMed Scopus (74) Google Scholar). AKR1B10 is primarily expressed in the colon and small intestine with low levels in the liver, thymus, prostate, and testis (1Cao D. Fan S.T. Chung S.S. J. Biol. Chem. 1998; 273: 11429-11435Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). However, this gene is overexpressed in 54% of human hepatocellular carcinoma, 84.4% of lung squamous cell carcinoma, and 29.2% of lung adenocarcinoma in smokers, making it a potential diagnostic and/or prognostic marker (1Cao D. Fan S.T. Chung S.S. J. Biol. Chem. 1998; 273: 11429-11435Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 6Penning T.M. Clin. Cancer Res. 2005; 11: 1687-1690Crossref PubMed Scopus (87) Google Scholar, 7Fukumoto S. Yamauchi N. Moriguchi H. Hippo Y. Watanabe A. Shibahara J. Taniguchi H. Ishikawa S. Ito H. Yamamoto S. Iwanari H. Hironaka M. Ishikawa Y. Niki T. Sohara Y. Kodama T. Nishimura M. Fukayama M. Dosaka-Akita H. Aburatani H. Clin. Cancer Res. 2005; 11: 1776-1785Crossref PubMed Scopus (244) Google Scholar). AKR1B10 is an enzyme that efficiently catalyzes the reduction of carbonyls to corresponding alcohols with NADPH as a co-enzyme (1Cao D. Fan S.T. Chung S.S. J. Biol. Chem. 1998; 273: 11429-11435Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). Recent studies demonstrate that AKR1B10 expression facilitates growth of cancer cells, enhances their clonogenic capability, and reduces their susceptibility to reactive carbonyls such as acrolein and crotonaldehyde (8Zu X. Yan R. Robbins S. Krishack P.A. Liao D.F. Cao D. Toxicol. Sci. 2007; 97: 562-568Crossref PubMed Scopus (39) Google Scholar, 9Yan R. Zu X. Ma J. Liu Z. Adeyanju M. Cao D. Int. J. Cancer. 2007; 121: 2301-2306Crossref PubMed Scopus (123) Google Scholar). In vitro, AKR1B10 also shows strong enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal, reducing them to the corresponding retinols. The diversity of retinal metabolism may diminish intracellular retinoic acid, a signaling molecule regulating cell proliferation and differentiation (4Crosas B. Hyndman D.J. Gallego O. Martras S. Pares X. Flynn T.G. Farres J. Biochem. J. 2003; 373: 973-979Crossref PubMed Google Scholar, 10Dragnev K.H. Rigas J.R. Dmitrovsky E. Oncologist. 2000; 5: 361-368Crossref PubMed Scopus (104) Google Scholar). aldo-keto reductase family 1 B10 acetyl-CoA carboxylase-α enhanced green fluorescent protein human mammary epithelial cell small-interfering RNA nickel-nitrilotriacetic acid. The current study presents a novel biological function of AKR1B10, regulating long chain fatty acid synthesis, in human breast cancer cells. During tumorigenic transformation of human mammary epithelial cells (HMEC), AKR1B10 is up-regulated and associates with acetyl-CoA carboxylase-α (ACCA). ACCA is a rate-limiting enzyme of de novo synthesis of long chain fatty acids, catalyzing the formation of malonyl-CoA by ATP-dependent carboxylation of acetyl-CoA (11Witters L.A. Widmer J. King A.N. Fassihi K. Kuhajda F. Int. J. Biochem. 1994; 26: 589-594Crossref PubMed Scopus (50) Google Scholar, 12Zang Y. Wang T. Xie W. Wang-Fischer Y.L. Getty L. Han J. Corkey B.E. Guo W. Obes. Res. 2005; 13: 1530-1539Crossref PubMed Scopus (36) Google Scholar). Increased lipogenesis is an important characteristic of cancer cells and likely contributes to the development and progression of cancer, but the regulatory mechanisms remain to be elucidated (13Rouquette-Jazdanian A.K. Pelassy C. Breittmayer J.P. Cousin J.L. Aussel C. Biochem. J. 2002; 363: 645-655Crossref PubMed Google Scholar, 14Swinnen J.V. Heemers H. van de Sande T. de Schrijver E. Brusselmans K. Heyns W. Verhoeven G. J. Steroid Biochem. Mol. Biol. 2004; 92: 273-279Crossref PubMed Scopus (131) Google Scholar). Up-regulation of lipogenic enzymes such as fatty acid synthase and ACCA has been documented in a variety of cancers, including breast, prostate, ovary, lung, colon, and endometrial cancers (11Witters L.A. Widmer J. King A.N. Fassihi K. Kuhajda F. Int. J. Biochem. 1994; 26: 589-594Crossref PubMed Scopus (50) Google Scholar, 14Swinnen J.V. Heemers H. van de Sande T. de Schrijver E. Brusselmans K. Heyns W. Verhoeven G. J. Steroid Biochem. Mol. Biol. 2004; 92: 273-279Crossref PubMed Scopus (131) Google Scholar, 15Kuhajda F.P. Nutrition. 2000; 16: 202-208Crossref PubMed Scopus (672) Google Scholar, 16Swinnen J.V. Roskams T. Joniau S. Van Poppel H. Oyen R. Baert L. Heyns W. Verhoeven G. Int. J. Cancer. 2002; 98: 19-22Crossref PubMed Scopus (301) Google Scholar, 17Rossi S. Graner E. Febbo P. Weinstein L. Bhattacharya N. Onody T. Bubley G. Balk S. Loda M. Mol. Cancer Res. 2003; 1: 707-715PubMed Google Scholar, 18Milgraum L.Z. Witters L.A. Pasternack G.R. Kuhajda F.P. Clin. Cancer Res. 1997; 3: 2115-2120PubMed Google Scholar, 19Yahagi N. Shimano H. Hasegawa K. Ohashi K. Matsuzaka T. Najima Y. Sekiya M. Tomita S. Okazaki H. Tamura Y. Iizuka Y. Ohashi K. Nagai R. Ishibashi S. Kadowaki T. Makuuchi M. Ohnishi S. Osuga J. Yamada N. Eur. J. Cancer. 2005; 41: 1316-1322Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). Long chain fatty acids are building blocks of membranes and precursors of lipid second messengers, playing a critical role in cell proliferation and division; ACCA knock-out mice are embryonically lethal (20Swinnen J.V. Brusselmans K. Verhoeven G. Curr. Opin. Clin. Nutr. Metab. Care. 2006; 9: 358-365Crossref PubMed Scopus (476) Google Scholar, 21Abu-Elheiga L. Matzuk M.M. Kordari P. Oh W. Shaikenov T. Gu Z. Wakil S.J. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12011-12016Crossref PubMed Scopus (196) Google Scholar). In prostate and breast cancer cells, RNA interference-mediated silencing of ACCA inhibits fatty acid synthesis, arrests cell cycle, and induces caspase-mediated apoptosis (22Chajes V. Cambot M. Moreau K. Lenoir G.M. Joulin V. Cancer Res. 2006; 66: 5287-5294Crossref PubMed Scopus (288) Google Scholar, 23Brusselmans K. De Schrijver E. Verhoeven G. Swinnen J.V. Cancer Res. 2005; 65: 6719-6725Crossref PubMed Scopus (243) Google Scholar, 24Tong L. Harwood Jr., H.J. J. Cell. Biochem. 2006; 99: 1476-1488Crossref PubMed Scopus (165) Google Scholar). This study identifies AKR1B10 as a novel regulator of fatty acid de novo synthesis, providing a new target for the manipulation of cancer cell growth. Cell Culture and AKR1B10 Silencing by siRNARAO-1, RAO-2, and RAO-3 cells were cultured in DFCI-1 medium characterized previously (25Cheng J.M. Ding M. Aribi A. Shah P. Rao K. Int. J. Cancer. 2006; 118: 2957-2964Crossref PubMed Scopus (63) Google Scholar). For AKR1B10 gene silencing, small-interfering RNAs (siRNA) were synthesized and introduced into RAO-3 cells as described previously (9Yan R. Zu X. Ma J. Liu Z. Adeyanju M. Cao D. Int. J. Cancer. 2007; 121: 2301-2306Crossref PubMed Scopus (123) Google Scholar). Gel Filtration30 ml of Sephacryl-S 300 (Amersham Biosciences) was packed into a column (10 × 300 mm) following the product instructions. RAO-3 cells (1 × 108) were lysed in a buffer (0.2% Nonidet P-40, 1 mm phenylmethylsulfonyl fluoride, 1 mm leupeptin, 150 mm NaCl, 2 mm EDTA, 50 mm Tris-HCl, pH 7.0, and 10% glycerol) (26Moreau K. Dizin E. Ray H. Luquain C. Lefai E. Foufelle F. Billaud M. Lenoir G.M. Venezia N.D. J. Biol. Chem. 2006; 281: 3172-3181Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar) After centrifugation at 10,000 × g, 4 °C for 20 min, soluble proteins were loaded to the column at 4 °C. Proteins were eluted with 10 mm KCl in 20 mm Tris-HCl, pH 7.0, at 0.2 ml/min and collected at 0.5 ml/fraction. Ferritin (440 kDa), yeast alcohol dehydrogenase (150 kDa), bovine albumin (67 kDa), and carbonic anhydrase (29 kDa) were used as standards. Anion Exchanger ChromatographyTotal volume of 2 ml of DEAE-Sepharose (Amersham Biosciences) was packed into a column. RAO-3 cells were lysed in the buffer as described above. Soluble proteins were applied to the column connected to a fast protein liquid chromatography system (Bio-Rad) at 0.25 ml/min. Flow-through was collected. After being washed with 10 column volumes of lysis buffer, binding proteins were eluted with NaCl at a gradient of 10 to 1000 mm and collected at 0.5 ml/fraction. Co-immunoprecipitationRAO-3 cells were lysed as above. Soluble proteins (500 μg) were incubated with 5 μg of anti-AKR1B10 (refer tosupplemental data for activity and specificity of AKR1B10 antibody produced in our laboratory) or 5 μg of anti-ACCA (Cell Signaling) antibodies at 4 °C overnight, followed by incubation with 40 μl of slurry-Sepharose protein A/G beads at 4 °C for 1 h with gentle shaking. Beads were collected by brief centrifugation and washed five times with lysis buffer (see above). Proteins were eluted with 50 μl of 100 mm glycine, pH 2.5, and separated on 8–12% SDS-PAGE, followed by Coomassie Blue staining or Western blot. Rabbit IgG (5 μg) was used as a negative control. Mass Spectrometry AssayCo-purified protein by immunoprecipitation was collected from SDS-PAGE. Gel slices were destained and digested in 25 μl of sequencing grade trypsin (12.5 ng/μl in 25 mm ammonium bicarbonate; G-Biosciences) at 37 °C overnight. The digested sample was dried using a Savant SpeedVac concentrator and resuspended in 13 μl of 5% acetonitrile containing 0.1% formic acid. 10 μl of sample was used for mass spectrometry analysis. A quadruple time-of-flight mass spectrometer (Waters DEME-ToF) connected to a Waters nano Acquity UPLC was used for mass spectrometry analysis. Column used was Waters Atlantis C-18 (0.03-mm particle, 0.075 × 150 mm). Flow rate was at 250 nl/min. Peptides were eluted using a linear gradient of water/acetonitrile containing 0.1% formic acid from water to acetonitrile in 60 min. The mass spectrometer was set for data-dependent acquisition; tandem mass spectrometry was performed on the top three peaks at any given time. Data analysis was done using Waters Protein Lynx Global Server 2.2.5, MASCOT (Matrix Sciences) and PEAKS (Bioinformatics Solutions Inc. Waterloo, ON, Canada), and blasted against the NCBI NR data base. Western Blot AnalysisWestern blot was performed as previously described (8Zu X. Yan R. Robbins S. Krishack P.A. Liao D.F. Cao D. Toxicol. Sci. 2007; 97: 562-568Crossref PubMed Scopus (39) Google Scholar). ACCA antibody was used at 1:1000 in blocking buffer (Li-Cor Biosciences). Recombinant AKR1B10 Protein Preparation and Pulldown AssayRecombinant AKR1B10 protein with His tag was purified as described previously (8Zu X. Yan R. Robbins S. Krishack P.A. Liao D.F. Cao D. Toxicol. Sci. 2007; 97: 562-568Crossref PubMed Scopus (39) Google Scholar). (Refer tosupplemental data for quality of protein.) To perform pulldown assay, 5 μg of recombinant AKR1B10 protein was incubated with 500 μg of soluble protein (cell lysates) at 4 °C for 2 h. Ni-NTA-agarose beads (40 μl) were then added and incubated at 4 °C for 1 h. After brief centrifugation, Ni-NTA-agarose beads were pelleted and washed with lysis buffer (see above) five times. Proteins were released by heating at 95 °C in 5× SDS-PAGE loading buffer for 3 min and subjected to Western blot. A Ni-NTA-agarose was in and protein expression was into RAO-3 cells as previously described (8Zu X. Yan R. Robbins S. Krishack P.A. Liao D.F. Cao D. Toxicol. Sci. 2007; 97: 562-568Crossref PubMed Scopus (39) Google Scholar). After for cells were in for 10 min and then in for 1 min, followed by incubation with ACCA antibody at 4 °C overnight. antibody was used to ACCA by was performed for and of and ACCA acid synthesis was by acid In cells were with 1 of acid for 4 h. were and washed with three times. of the cell was lysed for protein with protein The was with 20 volumes of After incubation on for 10 min, was at × for 10 min, and was washed with 0.2 volume of and were and was dried in were in ml of liquid and was by a analysis was performed using with the analysis was as AKR1B10 and ACCA are in a a of cell (25Cheng J.M. Ding M. Aribi A. Shah P. Rao K. Int. J. Cancer. 2006; 118: 2957-2964Crossref PubMed Scopus (63) Google Scholar). cells were by a of cells. of into cells, and RAO-3 cells were cells with expression growth but are tumorigenic in RAO-3 cells an of gene expression and growth in and in In this a of AKR1B10 and ACCA proteins in RAO-3 cells AKR1B10 Protein in RAO-3 the biological function of the AKR1B10 protein in the tumorigenic RAO-3 cells, in gel filtration chromatography two AKR1B10 protein peaks with of and To this exchange chromatography was using DEAE-Sepharose ion exchange column. In this assay, AKR1B10 protein was in two distinct A of AKR1B10 in the bound to the column with at mm NaCl the the gel filtration column that AKR1B10 in the of The AKR1B10 bound to ion exchange column for the at These data the of two distinct AKR1B10 in RAO-3 cells, monomers with mass of and complexes with a mass of that with AKR1B10 with ACCA in RAO-3 proteins that with AKR1B10, immunoprecipitation was performed with a anti-AKR1B10 antibody in our data demonstrate the activity and specificity of AKR1B10 After on SDS-PAGE, Coomassie Blue staining a protein at was in the IgG AKR1B10 in was confirmed by Western blot Protein mass spectrometry analysis identified that this protein is ACCA with 4 shows an of mass spectrometry analysis of acids association with AKR1B10 also ACCA binding to DEAE-Sepharose protein in 3 was identified as acetyl-CoA carboxylase-α using mass was by de novo sequencing using the and confirmed the corresponding to for acetyl-CoA of AKR1B10 with ACCA was confirmed by co-immunoprecipitation using antibody and AKR1B10 protein pulldown In RAO-3 cells, AKR1B10 protein was by ACCA antibody and ACCA was down by recombinant AKR1B10 protein (Refer to data for the quality of AKR1B10 recombinant protein.) In intracellular fluorescent studies showed that with ACCA protein in the cytoplasm of RAO-3 cells AKR1B10 protein was into RAO-3 cells on After incubation for ACCA protein was by and with antibodies as described and by a of and ACCA proteins in RAO-3 AKR1B10 in RAO-3 by ACCA through the biological of this further the of AKR1B10 knock down on ACCA protein and de novo fatty acid synthesis. ACCA protein degradation in RAO-3 cells. shows that RAO-3 cells to a resulted in a of ACCA degradation through ubiquitination-proteasome pathway as previously L. Heredia R. N. S. J. C. M. J. M. 2006; PubMed Scopus Google Scholar, J.M. 2006; PubMed Scopus Google Scholar). AKR1B10 protein in RAO-3 cells with synthesized 1 and 2 characterized in our studies (9Yan R. Zu X. Ma J. Liu Z. Adeyanju M. Cao D. Int. J. Cancer. 2007; 121: 2301-2306Crossref PubMed Scopus (123) Google Scholar) and ACCA protein in AKR1B10 knock down a decrease of ACCA protein This ACCA protein reduction was by that by association AKR1B10 ACCA degradation through ubiquitination-proteasome the of AKR1B10 knock down on de novo fatty acid synthesis in RAO-3 cells by the of acid. The showed that AKR1B10 knock down resulted in >50% decrease of fatty acid data suggest that AKR1B10 fatty acid synthesis regulating ACCA are of cancer In of cancers, lipogenic such as fatty acid synthase and ACCA are up-regulated J.V. Heemers H. van de Sande T. de Schrijver E. Brusselmans K. Heyns W. Verhoeven G. J. Steroid Biochem. Mol. Biol. 2004; 92: 273-279Crossref PubMed Scopus (131) Google Scholar, 15Kuhajda F.P. Nutrition. 2000; 16: 202-208Crossref PubMed Scopus (672) Google Scholar, 16Swinnen J.V. Roskams T. Joniau S. Van Poppel H. Oyen R. Baert L. Heyns W. Verhoeven G. Int. J. Cancer. 2002; 98: 19-22Crossref PubMed Scopus (301) Google Scholar). For fatty acid synthase is overexpressed in the of prostate transformation and expression levels are to the of and J.V. Roskams T. Joniau S. Van Poppel H. Oyen R. Baert L. Heyns W. Verhoeven G. Int. J. Cancer. 2002; 98: 19-22Crossref PubMed Scopus (301) Google Scholar, PubMed Scopus Google Scholar). Recent studies have demonstrated that in cells synthesized are the of cell the of cell More synthesized are with or fatty fatty acids to into or cell and intracellular (13Rouquette-Jazdanian A.K. Pelassy C. Breittmayer J.P. Cousin J.L. Aussel C. Biochem. J. 2002; 363: 645-655Crossref PubMed Google Scholar, 14Swinnen J.V. Heemers H. van de Sande T. de Schrijver E. Brusselmans K. Heyns W. Verhoeven G. J. Steroid Biochem. Mol. Biol. 2004; 92: 273-279Crossref PubMed Scopus (131) Google Scholar, K. D. Mol. Cell. Biol. 2000; 1: PubMed Scopus Google Scholar, S. E. C. P. J.P. J. PubMed Scopus Google Scholar). In this that AKR1B10 is up-regulated in tumorigenic RAO-3 cells and in ACCA and fatty acid synthesis, role in cancer This study of AKR1B10 protein up-regulated in RAO-3 cells with gel filtration and DEAE-Sepharose ion exchange The demonstrated that AKR1B10 protein exists in two distinct in RAO-3 cells. (∼40 kDa) bound to the DEAE-Sepharose column the (∼300 kDa) in flow-through. The is a protein with ion exchange pulldown assay, and mass spectrometry that ACCA kDa) is the protein with AKR1B10 in RAO-3 cells, and AKR1B10 with demonstrated a with ACCA protein. were in cells, a colon adenocarcinoma cell ACCA catalyzes the carboxylation of is the rate-limiting of de novo fatty acid synthesis Y. Wang T. Xie W. Wang-Fischer Y.L. Getty L. Han J. Corkey B.E. Guo W. Obes. Res. 2005; 13: 1530-1539Crossref PubMed Scopus (36) Google Scholar). In ACCA activity is by and The is by such as and growth A.N. Biochem. 2006; PubMed Google Scholar, S. J. Res. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. N. Eur. J. Biochem. PubMed Scopus Google Scholar). In breast cancer cells, breast cancer 1 the tandem at associates with ACCA and enzymatic activity by blocking from fatty acid synthesis (26Moreau K. Dizin E. Ray H. Luquain C. Lefai E. Foufelle F. Billaud M. Lenoir G.M. Venezia N.D. J. Biol. Chem. 2006; 281: 3172-3181Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, C. R. A. M. S. Lenoir G.M. Venezia N.D. 2002; PubMed Scopus Google Scholar). To the function of AKR1B10 protein using two that target the and of AKR1B10 These two were characterized in our in and knock down of AKR1B10 (9Yan R. Zu X. Ma J. Liu Z. Adeyanju M. Cao D. Int. J. Cancer. 2007; 121: 2301-2306Crossref PubMed Scopus (123) Google Scholar). In this AKR1B10 knock down a decrease of ACCA protein and reduction of fatty acid synthesis. The that ACCA protein degradation by AKR1B10 silencing was by a that AKR1B10 to ACCA and degradation through the ubiquitination-proteasome These data a novel regulatory of ACCA activity and fatty acid synthesis. studies are in to the and binding in In this study for the that AKR1B10, in tumorigenic cells, fatty acid synthesis by regulating the of ACCA protein and a novel target for the of de novo fatty acid synthesis in cancer cells. with

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