AKR1B10 is a human nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase belonging to the aldo-keto reductase (AKR) 1B subfamily. It catalyzes the reduction of aldehydes, some ketones and quinones, and interacts with acetyl-CoA carboxylase and heat shock protein 90α. The enzyme is highly expressed in epithelial cells of the stomach and intestine, but down-regulated in gastrointestinal cancers and inflammatory bowel diseases. In contrast, AKR1B10 expression is low in other tissues, where the enzyme is upregulated in cancers, as well as in non-alcoholic fatty liver disease and several skin diseases. In addition, the enzyme’s expression is elevated in cancer cells resistant to clinical anti-cancer drugs. Thus, growing evidence supports AKR1B10 as a potential target for diagnosing and treating these diseases. Herein, we reviewed the literature on the roles of AKR1B10 in a healthy gastrointestinal tract, the development and progression of cancers and acquired chemoresistance, in addition to its gene regulation, functions, and inhibitors.
Aldo-keto reductases (AKRs) are a group of NAD(P)(H)-dependent enzymes catalyzing interconversions between the carbonyl and alcohol groups of endogenous and xenobiotic compounds . The AKR superfamily is systematized into 16 families: AKR1 (aldehyde reductases, aldose reductases, hydroxysteroid dehydrogenases, and steroid 5b-reductases); AKR2 (mannose and xylose reductases); AKR3 (yeast AKRs); AKR4 (chalcone and codeinone reductases); AKR5 (gluconic acid reductases); AKR6 (β-subunits of the potassiumgated voltage channels); AKR7 (aflatoxin dialdehyde and succinic semialdehyde reductases); AKR8 (pyridoxal reductases); AKR9 (aryl alcohol dehydrogenases); AKR10 (Streptomyces AKRs); AKR11 (Bacillus AKRs); AKR12 (Streptomyces sugar aldehyde reductases); AKR13 (hyperthermophilic bacteria reductases); AKR14 (Escherichia coli reductases), AKR15 (Mycobacterium reductases), and AKR16 (Vibrio cholerae reductases). Each family is further divided into several subfamilies based on a >60% amino acid sequence identity. To date, fifteen AKR members have been identified in humans and belong to the AKR1A, AKR1B, AKR1C, AKR1E, AKR6A, and AKR7A subfamilies. There are three members of the human AKR1B subfamily: AKR1B1 (aldose reductase), AKR1B10 (aldose reductase-like protein-1), and AKR1B15, whose genes are clustered at chromosome 7q33 . AKR1B1, AKR1B10, and an enzymatically active isoform of AKR1B15 are 36-kDa soluble monomeric proteins consisting of 316 amino acids and sharing >68% amino acid sequence identity, of which 91.5% are shared between AKR1B10 and AKR1B15 . The three AKRs are NADPH-dependent reductases and display overlapping substrate specificities for aromatic and aliphatic aldehydes but differ in their catalytic efficiencies , which is notably higher for retinal (all-trans-retinaldehyde) in AKR1B10 . In addition, the glucose reductase activity characteristics of AKR1B1 are very low for AKR1B10 and AKR1B15 , and prostaglandin F synthase activity is observed with AKR1B1, but not with AKR1B10 . In contrast to AKR1B1, AKR1B10 and AKR1B15 exhibit low 17β-hydroxysteroid dehydrogenase activity for estrone and 4-androstene-3,17-dione . For subcellular localization, AKR1B1 and AKR1B10 are cytosolic, whereas AKR1B15 is in the mitochondria . The three AKR1Bs also have different tissue distributions. While AKR1B1 is ubiquitous, AKR1B10 protein is predominantly expressed in the human stomach and intestine , although its mRNA is detected in many other tissues . The mRNA for AKR1B15 is predominantly expressed in the placenta, testis, skeletal muscle, and adipose tissue, where its level is lower than that of mRNA for AKR1B10 .
|Agent *||Signal Molecule||Cell **||References|
|Ethoxyquin||Nrf2||Lung cancer A549, H23|||
|MG-132, bortezomib||Nrf2||CRC SW-480, HT29|||
|Doxorubicin||Nrf2||Gastric cancer MKN45|||
|EGF, insulin||AP-1, ERK||HCC HepG2, Hep3B|||
|Lipopolysaccharide||Blood mononuclear cells|||
|BMP, IBMX||Mesenchymal stem cells|||
|9,10-Phenanthrenequinone||Nrf2, ERK||Lung cancer A549|||
|Cigarette smoke extract||Airway epithelium|||
|Carnosic acid, t-BHQ||Nrf2||Astrocytoma U373MG|||
|5-FU, L-OHP||p53||CRC HT116|||
|TPA||c-Jun, ERK||Lung cancer A549|||
|5-FU, L-OHP||CRC HT29|||