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Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-alpha in breast cancer cells.

Abstract
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 (approximately 40 kDa) bound to DEAE-Sepharose column and protein complexes (approximately 300 kDa) remaining in flow-through. Co-immunoprecipitation with AKR1B10 antibody and protein mass spectrometry analysis identified that AKR1B10 associates with acetyl-CoA carboxylase-alpha (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.
AuthorsJun Ma, Ruilan Yan, Xuyu Zu, Ji-Ming Cheng, Krishna Rao, Duan-Fang Liao, Deliang Cao
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 6 Pg. 3418-3423 (Feb 08 2008) ISSN: 0021-9258 [Print] United States
PMID18056116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Fatty Acids
  • RNA, Small Interfering
  • Recombinant Proteins
  • Ubiquitin
  • AKR1B10 protein, human
  • Aldo-Keto Reductases
  • Aldehyde Reductase
  • Proteasome Endopeptidase Complex
  • Acetyl-CoA Carboxylase
Topics
  • Acetyl-CoA Carboxylase (chemistry, metabolism)
  • Aldehyde Reductase (genetics, physiology)
  • Aldo-Keto Reductases
  • Breast Neoplasms (metabolism)
  • Cell Line, Tumor
  • Cell Membrane (metabolism)
  • Cytoplasm (metabolism)
  • Fatty Acids (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Proteasome Endopeptidase Complex (metabolism)
  • RNA, Small Interfering (metabolism)
  • Recombinant Proteins (chemistry)
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Ubiquitin (metabolism)

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