Aldo-keto reductases from the AKR1B subfamily: Retinoid specificity and control of cellular retinoic acid levels

Ruiz, Francesc Xavier; Gallego, Oriol; Ardèvol, Albert; Moro, Armando; Domínguez, Marta; Álvarez, Susana; Álvarez, Rosana; Lera, Ángel R. de; Rovira, Carme; Fita, Ignacio; Parés, Xavier; Farrés, Jaume

doi:10.1016/j.cbi.2008.10.027

Cited by 69 publications

(67 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10 AKR1B10 is the most active AKR to modify all-transretinal, with a catalytic turnover constant/km value about 100-fold higher than other AKRs. 8,10 …”

Section: Discussionmentioning

confidence: 99%

“…many members of the AKR family is AKR1B10, an enzyme with a preference for eliminating retinals. [8][9][10] AKR1B10 is normally expressed in the small intestine and colon, with low-level expression in the liver but not in the lung. 11 However, a number of studies have demonstrated that it is overexpressed in smokers with non-small cell lung cancer (NSCLC), suggesting that AKR1B10 may be a useful marker for NSCLC.…”

Section: Rna Extraction Microarray Processing and Data Analysismentioning

confidence: 99%

“…33,34 The third is supported by in vitro and in vivo studies demonstrating the activity of AKR1B10 in retinoic acid metabolism. 8,10 Because retinoic acid is the vital factor in human airway epithelial differentiation, a local deficiency of retinoic acid promotes squamous metaplasia and carcinogenesis of the airway epithelium. 14,15 The data demonstrating that overexpression of AKR1B10 resulted in preferential conversion of exogenous retinal to retinol are consistent with this third mechanism.…”

Section: Akr1b10mentioning

confidence: 99%

See 2 more Smart Citations

Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals

Wang

Ricard

et al. 2010

Chest

View full text Add to dashboard Cite

T he aldo-keto reductase (AKR) superfamily includes a group of monomeric 37-kDa soluble reduced nicotinamide adenine dinucleotide phosphate-dependent oxidoreductases that function in elimination reactions by modifying carbonyl groups on aldehyde or ketones to form primary or secondary alcohols, which are then conjugated with sulfates or glucuronide for excretion. [1][2][3][4][5][6] Like the cytochrome P450 superfamily, the AKRs are classifi ed as a phase 1 drug, xenobiotic and carcinogen-metabolizing enzymes. 7 One of the Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy IndividualsRui Wang , MD , PhD ; Guoqing Wang , PhD ; Megan J. Ricard , MS ; Barbara Ferris , BA ; Yael Strulovici-Barel , MSc ; Jacqueline Salit , MS ; Neil R. Hackett , PhD ; Lorraine J. Gudas , PhD ; and Ronald G. Crystal Background: The aldo-keto reductase (AKR) gene superfamily codes for monomeric, soluble reduced nicotinamide adenine dinucleotide phosphate-dependent oxidoreductases that mediate elimination reactions. AKR1B10, an AKR that eliminates retinals, has been observed as upregulated in squamous metaplasia and non-small cell lung cancer and has been suggested as a diagnostic marker specifi c to tobacco-related carcinogenesis. We hypothesized that upregulation of AKR1B10 expression may be initiated in healthy smokers prior to the development of evidence of lung cancer. Methods: Expression of AKR1B10 was assessed at the mRNA level using microarrays with TaqMan confi rmation in the large airway epithelium (21 healthy nonsmokers, 31 healthy smokers) and small airway epithelium (51 healthy nonsmokers, 58 healthy smokers) obtained by fi beroptic bronchoscopy and brushing. Results: Compared with healthy nonsmokers, AKR1B10 mRNA levels were signifi cantly upregulated in both large and small airway epithelia of healthy smokers. Consistent with the mRNA data, AKR1B10 protein was signifi cantly upregulated in the airway epithelium of healthy smokers as assessed by Western blot analysis and immunohistochemistry, with AKR1B10 expressed in both differentiated and basal cells. Finally, cigarette smoke extract mediated upregulation of AKR1B10 in airway epithelial cells in vitro, and transfection of AKR1B10 into airway epithelial cells enhanced the conversion of retinal to retinol. Conclusions: Smoking per se mediates upregulation of AKR1B10 expression in the airway epithelia of healthy smokers with no evidence of lung cancer. In the context of these observations and the link of AKR1B10 to the metabolism of retinals and to lung cancer, the smoking-induced upregulation of AKR1B10 may be an early process in the multiple events leading to lung cancer.

show abstract

“…10 AKR1B10 is the most active AKR to modify all-transretinal, with a catalytic turnover constant/km value about 100-fold higher than other AKRs. 8,10 …”

Section: Discussionmentioning

confidence: 99%

Section: Rna Extraction Microarray Processing and Data Analysismentioning

confidence: 99%

Section: Akr1b10mentioning

confidence: 99%

See 1 more Smart Citation

Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals

Wang

Ricard

et al. 2010

Chest

View full text Add to dashboard Cite

show abstract

“…Retinoic acid is an important signaling molecule which directs cell differentiation. AKR1B10 can reduce retinal to retinol (thus limiting retinoic acid formation), therefore stimulating carcinogenesis by controlling the retinoid signaling pathway [7] . Under physiological conditions, highly reactive aldehyde and ketone groups lead to cell death by carbonylinduced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

et al. 2015

View full text Add to dashboard Cite

Aim: Recent evidence suggests that aldo-keto reductase family 1 B10 (AKR1B10) may be a potential diagnostic or prognostic marker of human tumors, and that AKR1B10 inhibitors offer a promising choice for treatment of many types of human cancers. The aim of this study was to identify novel chemical scaffolds of AKR1B10 inhibitors using in silico approaches. Methods: The 3D QSAR pharmacophore models were generated using HypoGen. A validated pharmacophore model was selected for virtual screening of 4 chemical databases. The best mapped compounds were assessed for their drug-like properties. The binding orientations of the resulting compounds were predicted by molecular docking. Density functional theory calculations were carried out using B3LYP. The stability of the protein-ligand complexes and the final binding modes of the hit compounds were analyzed using 10 ns molecular dynamics (MD) simulations. Results: The best pharmacophore model (Hypo 1) showed the highest correlation coefficient (0.979), lowest total cost (102.89) and least RMSD value (0.59). Hypo 1 consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one ring aromatic and one hydrophobic feature. This model was validated by Fischer's randomization and 40 test set compounds. Virtual screening of chemical databases and the docking studies resulted in 30 representative compounds. Frontier orbital analysis confirmed that only 3 compounds had sufficiently low energy band gaps. MD simulations revealed the binding modes of the 3 hit compounds: all of them showed a large number of hydrogen bonds and hydrophobic interactions with the active site and specificity pocket residues of AKR1B10. Conclusion: Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors.

show abstract

“…[6][7][8][9][10][11] AKR1B10 is also active to all-trans-retinal, a precursor of the signaling molecule retinoic acid that regulates cell proliferation and differentiation, and to polycyclic aromatic hydrocarbon, an environmental procarcinogen. [12][13][14][15] Recent studies from our and other laboratories showed that AKR1B10 can reduce the C13 ketonic group in daunorubicin and idarubicin, leading to chemoresistance of cancer cells to these cytostatic agents. 11,16,17 In human mammary epithelial cells in culture, AKR1B10 is upregulated with malignant transformation and blocks the ubiquitin-dependent degradation of acetyl-CoA carboxylase-a (ACCA), a rate-limiting enzyme in de novo fatty acid synthesis, promoting fatty acid/lipid synthesis.…”

mentioning

confidence: 99%

AKR1B10 overexpression in breast cancer: Association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker

Luo

Huang

et al. 2012

Intl Journal of Cancer

101

111

View full text Add to dashboard Cite

Aldo-keto reductase 1B10 (AKR1B10) is a secretory protein that is upregulated with tumorigenic transformation of human mammary epithelial cells. This study demonstrated that AKR1B10 was overexpressed in 20 (71.4%) of 28 ductal carcinomas in situ, 184 (83.6%) of 220 infiltrating carcinomas and 28 (87.5%) of 32 recurrent tumors. AKR1B10 expression in breast cancer was correlated positively with tumor size (p 5 0.0012) and lymph node metastasis (p 5 0.0123) but inversely with disease-related survival (p 5 0.0120). Univariate (p 5 0.0077) and multivariate (p 5 0.0192) analyses both suggested that AKR1B10, alone or together with tumor size and node status, is a significant prognostic factor for breast cancer. Silencing of AKR1B10 in BT-20 human breast cancer cells inhibited cell growth in culture and tumorigenesis in female nude mice. Importantly, AKR1B10 in the serum of breast cancer patients was significantly increased to 15.18 6 9.08 ng/ml [n 5 50; 95% confidence interval (CI), 12.60-17.76], with a high level up to 58.4 ng/ml, compared to 3.34 6 2.27 ng/ml in healthy donors (n 5 60; 95% CI, 2.78-3.90). In these patients, AKR1B10 levels in serum were correlated with its expression in tumors (r 5 0.8066; p < 0.0001). Together our data suggests that AKR1B10 is overexpressed in breast cancer and may be a novel prognostic factor and serum marker for this deadly disease.

show abstract

Aldo-keto reductases from the AKR1B subfamily: Retinoid specificity and control of cellular retinoic acid levels

Cited by 69 publications

References 65 publications

Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals

Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

AKR1B10 overexpression in breast cancer: Association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker

Contact Info

Product

Resources

About