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Publication
Journal: Journal of Steroid Biochemistry and Molecular Biology
July/17/2017
Abstract
Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential of STAR and AKR1B10 as prognostic biomarkers, which calls for further validation at the protein level.
Publication
Journal: Breast
March/9/2017
Abstract
The incidence of breast cancer in India is on the rise and is rapidly becoming the primary cancer in Indian women. The aldoketo reductase (AKR) family has more than 190 proteins including aldose reductase (AKR1B1) and aldose reductase like protein (AKR1B10). Apart from liver cancer, the status of AKR1B1 and AKR1B10 with respect to their expression and activity has not been reported in other human cancers. We studied the specific activity and expression of AKR1B1 and AKR1B10 in breast non tumor and tumor tissues and in the blood. Fresh post-surgical breast cancer and non-cancer tissues and blood were collected from the subjects who were admitted for surgical therapy. Malignant, benign and pre-surgical chemotherapy samples were evaluated by histopathology scoring. Expression of AKR1B1 and AKR1B10 was carried out by immunoblotting and immunohistochemistry (IHC) while specific activity was determined spectrophotometrically. The specific activity of AKR1B1 was significantly higher in red blood cells (RBC) in all three grades of primary surgical and post-chemotherapy samples. Specific activity of both AKR1B1 and AKR1B10 increased in tumor samples compared to their corresponding non tumor samples (primary surgical and post-chemotherapy). Immunoblotting and IHC data also indicated overexpression of AKR1B1 in all grades of tumors compared to their corresponding non tumor samples. There was no change in the specific activity of AKR1B1 in benign samples compared to all grades of tumor and non-tumors.
Publication
Journal: Journal of Biological Chemistry
March/4/2014
Abstract
Aldo-keto reductase 1B10 (AKR1B10) protein is a new tumor biomarker in humans. Our previous studies have shown that AKR1B10 is secreted through a lysosome-mediated nonclassical pathway, leading to an increase in the serum of breast cancer patients. This study illuminates the regulatory mechanism of AKR1B10 secretion. The cytosolic AKR1B10 associates with and is translocated to lysosomes by heat shock protein 90α (HSP90α), a chaperone molecule. Ectopic expression of HSP90α significantly increased the secretion of endogenous AKR1B10 and exogenous GFP-AKR1B10 fusion protein when cotransfected. Geldanamycin, a HSP90α inhibitor, dissociated AKR1B10-HSP90α complexes and significantly reduced AKR1B10 secretion in a dose-dependent manner. We characterized the functional domain in AKR1B10 and found that helix 10 (amino acids 233-240), located at the C terminus, regulates AKR1B10 secretion. Targeted point mutations recognized that amino acids Lys-233, Glu-236, and Lys-240 in helix 10 mediate the interaction of AKR1B10 with HSP90α. Together, our data suggest that HSP90α mediates AKR1B10 secretion through binding to its helix 10 domain. This finding is significant in exploiting the use of AKR1B10 in cancer clinics.
Publication
Journal: Biological and Pharmaceutical Bulletin
April/3/2013
Abstract
A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently identified as both diagnostic marker and therapeutic target in the treatment of several types of cancer. In this study, we have examined AKR1B10 inhibition by five xanthone derivatives, components of pericarps of mangosteen, of which α- and γ-mangostins show potential anti-cancer properties. Among the five xanthones, γ-mangostin was found to be the most potent competitive inhibitor (inhibition constant, 5.6 nM), but its 7-methoxy derivative, α-mangostin, was the second potent inhibitor (inhibition constant, 80 nM). Molecular docking of the two mangostins in AKR1B10 and site-directed mutagenesis of the putative binding residues revealed that Phe123, Trp220, Val301 and Gln303 are important for the tight binding of γ-mangostin, and suggested that the 7-methoxy group of α-mangostin impairs the inhibitory potency by altering the orientation of the inhibitor molecule in the substrate-binding site of the enzyme.
Publication
Journal: Cancer biomarkers : section A of Disease markers
May/11/2014
Abstract
BACKGROUND
Ductal carcinoma in situ of the breast constitutes the early stage of breast cancer when cancer cells are confined by the intact myoepithelial cell layer. Transition from DCIS to invasive carcinoma is a process yet poorly understood.
METHODS
By liquid chromatography (LC) and mass spectrometry (MS/MS) methods, we analyzed this early event using paired samples of micro-dissected cells overlaid with focally disrupted myoepithelial layers and their adjacent counterparts within the intact duct from formalin-fixed paraffin-embedded blocks.
RESULTS
AKR1B10, a member of Aldo-keto reductase family, was shown to be abundantly located in the filtering cells among a catalog of proteins. Moreover, strong correlation between AKR1B10 and HER2 positivity was found in an independent cohort of DCIS samples.
CONCLUSIONS
AKR1B10 could become a potential diagnosis and therapeutic marker for early breast cancers with HER2 overexpression and poor prognosis.
Publication
Journal: Acta crystallographica. Section D, Biological crystallography
August/19/2014
Abstract
Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (α/β)8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-NADP(+)-JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallographic structure of the corresponding AKR1B10-NADP(+)-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.
Publication
Journal: Clinical and Investigative Medicine
August/16/2009
Abstract
OBJECTIVE
Increased flux of glucose via the polyol pathway, oxidative stress and ischaemia lead to the upregulation of the aldose reductase (AR), the key enzyme of the polyol pathway. This adversely affects the organism and can in part be reduced by inhibition of the enzyme.
METHODS
In this study, we examined the effect of the HMG-CoA-reductase inhibitor atorvastatin on the expression of aldose reductase (AR, AKR1B1), aldehyde reductase (AldR, AKR1A1) and small intestine reductase (SIR, AKR1B10) in human umbilical vein endothelial cells (HUVEC) and human proximal tubular epithelial cells (PTEC) by RT-PCR.
RESULTS
In HUVEC, atorvastatin reduces the expression of aldehyde reductase and aldose reductase compared with control medium (-20% and -12% respectively, P < 0.05), while small intestine reductase is not expressed. In PTEC no regulation of aldehyde reductase and aldose reductase by atorvastatin could be measured, while the expression of small intestine reductase was reduced by 37% compared with control medium (P < 0.05). The reduction observed was not abolished by the addition of mevalonic acid.
CONCLUSIONS
The reduction of members of the aldo-keto-reductase family by atorvastatin is a novel way to influence the polyol pathway and a new pleiotropic effect of atorvastatin.
Publication
Journal: Medical Science Monitor
November/13/2018
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains difficult to diagnose at an early stage. Aldo-keto reductase family 1 member B10 (AKR1B10) is an oxidoreductase that is upregulated in some chronic liver diseases. The aim of this study was to use immunohistochemistry to evaluate the expression of AKR1B10 in liver tissue from patients with HCC of different stages. MATERIAL AND METHODS Forty-four patients with a tissue diagnosis of HCC (35 males and 9 females) with 37 control samples of liver tissue containing liver cirrhosis were studied using immunohistochemistry for the expression of AKR1B10. Histological examination determined the grade of HCC; the stage of HCC was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Serum alpha-fetoprotein (AFP) levels were measured and compared between the patients with HCC. RESULTS Immunohistochemistry showed increased expression of AKR1B10 in moderately-differentiated HCC compared with well-differentiated HCC, poorly-differentiated HCC, and liver cirrhosis (P<0.05). Sensitivity and specificity of AKR1B10 expression in HCC were high at a cutoff integral optical density (IOD) value of 89.5. A significant increase in AKR1B10 expression was found in early-stage HCC (P<0.05). Serum AFP levels were increased in patients with poorly-differentiated HCC, were increased in intermediate-stage HCC, and were significantly increased in advanced-stage HCC (P<0.05). CONCLUSIONS Immunohistochemistry showed that the expression of AKR1B10 was increased in tumor tissue from patients with early-stage HCC. Further studies are needed to determine the role of AKR1B10 in the early detection of HCC.
Publication
Journal: PLoS ONE
May/12/2016
Abstract
Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 is a well characterized enzyme with high retinaldehyde reductase activity, involved in the development of several cancer types, the enzymatic activity and physiological role of AKR1B15 are still poorly known. Here, the purified recombinant enzyme has been subjected to substrate specificity characterization, kinetic analysis and inhibitor screening, combined with structural modeling. AKR1B15 is active towards a variety of carbonyl substrates, including retinoids, with lower kcat and Km values than AKR1B10. In contrast to AKR1B10, which strongly prefers all-trans-retinaldehyde, AKR1B15 exhibits superior catalytic efficiency with 9-cis-retinaldehyde, the best substrate found for this enzyme. With ketone and dicarbonyl substrates, AKR1B15 also shows higher catalytic activity than AKR1B10. Several typical AKR inhibitors do not significantly affect AKR1B15 activity. Amino acid substitutions clustered in loops A and C result in a smaller, more hydrophobic and more rigid active site in AKR1B15 compared with the AKR1B10 pocket, consistent with distinct substrate specificity and narrower inhibitor selectivity for AKR1B15.
Publication
Journal: PLoS ONE
January/18/2016
Abstract
BACKGROUND
UNC50 has long been recognized as a Golgi apparatus protein in yeast, and is involved in nicotinic receptor trafficking in Caenorhabditis elegans, but little is known about UNC50 gene function in human biology despite it being conserved from yeast to high eukaryotes.
OBJECTIVE
We investigated the relation between UNC50 and human hepatocellular carcinoma (HCC) and the potential mechanisms underlying HCC development.
METHODS
UNC50 mRNA expression patterns in 12 HCC and adjacent non-cancerous tissues determined using northern blotting were confirmed by real-time PCR in another 44 paired tissues. Microarray experiments were used to screen for global effects of UNC50 knockdown in the Hep3B cell line, and were confirmed by real-time PCR, western blotting, flow cytometry, and tetrazolium assay in both UNC50 overexpression and knockdown Hep3B cells.
RESULTS
UNC50 expression levels were upregulated in HCC tissues in comparison with the adjacent non-cancerous tissues. UNC50 knockdown reduced mRNA levels of the downstream targets of the epidermal growth factor receptor (EGFR) pathway: cyclin D1 (CCND1), EGF, matrix metalloproteinase-7 (MMP7), aldose reductase-like 1 (AKR1B10), cell surface-associated mucin 1 (MUC1), and gastrin (GAST). Moreover, UNC50 influenced EGF, inducing cell cycle entry by affecting cell surface EGFR amounts.
CONCLUSIONS
UNC50 may plays some roles in HCC progression by affecting the EGFR pathway.
Publication
Journal: Oncology Letters
August/15/2017
Abstract
When assessing outcome in hepatocellular carcinoma (HCC), it is important to consider prognostic factors in background non-tumorous liver tissue as well as in the tumor, since multiple occurrence is associated with background liver status such as hepatitis. The current study aimed to elucidate molecular prognostic predictors that have an association with HCC background non-tumorous tissue. Microarray expression profiling identified aldo-keto reductase family 1, member B10 (<em>AKR1B10</em>) as a putative non-tumorous prognostic factor, and <em>AKR1B10</em> gene expression was investigated in 158 curatively resected HCC cases by reverse transcription-quantitative polymerase chain reaction. <em>AKR1B10</em> expression (<em>AKR1B10</em> value/GAPDH value × 1,000) was significantly higher in tumor tissue (median, 9.2200; range, 0.0003-611.0200; n=158) than in the corresponding non-tumorous tissue (median, 0.5461; range, 0.0018-69.0300; n=158) (P<0.001). When the samples were grouped according to <em>AKR1B10</em> expression in tumor tissue relative to non-tumorous tissue, tumor<non-tumorous expression (n=26) significantly correlated with poor recurrence-free survival (P=0.0074) and overall survival (OS) (P<0.0001), and was an independent prognostic factor for OS (P=0.0011) in a multivariate analysis. The ratio of <em>AKR1B10</em> messenger RNA levels in HCC and corresponding non-tumorous tissues may predict prognosis after curative hepatectomy, with low expression in HCC tissue relative to non-tumorous tissue indicative of poor prognosis.
Publication
Journal: Journal of Biological Chemistry
May/17/2015
Abstract
Aldo-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-keto-acyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues.
Publication
Journal: ChemMedChem
December/14/2014
Abstract
Caffeic acid phenethyl ester (CAPE), the major bioactive component of honeybee propolis, is a potent selective inhibitor of aldo-keto reductase family member 1B10 (AKR1B10), and a number of derivatives hold promise as potential anticancer agents. However, sequence homology between AKR1B10 and other members of the superfamily, including critical phase I metabolizing enzymes, has resulted in a concern over the selectivity of any potential therapeutic agent. To elucidate the binding mode of CAPE with AKR1B10 and to provide a tool for future in silico efforts towards identifying selective inhibitors, the crystal structure of AKR1B10 in complex with CAPE was determined. The observed interactions provide an explanation for the selectivity exhibited by CAPE for AKR1B10, and could be used to guide further derivative design.
Publication
Journal: Chemico-Biological Interactions
June/28/2015
Abstract
Aldose reductase (AR, AKR1B1) and AKR1B10 are enzymes implicated in important pathologies (diabetes and cancer) and therefore they have been proposed as suitable targets for drug development. Sulindac is the metabolic precursor of the potent non-steroidal anti-inflammatory drug (NSAID) sulindac sulfide, which suppresses prostaglandin production by inhibition of cyclooxygenases (COX). In addition, sulindac has been found to be one of the NSAIDs with higher antitumoral activity, presumably through COX inhibition. However, sulindac anticancer activity could be partially mediated through COX-independent mechanisms, including the participation of AR and AKR1B10. Previously, it had been shown that sulindac and sulindac sulfone were good AR inhibitors and the structure of the ternary complex with NADP(+) and sulindac was described (PDB ID 3U2C). In this work, we determined the three-dimensional structure of AKR1B10 with sulindac and established structure-activity relationships (SAR) of sulindac and their derivatives with AR and AKR1B10. The difference in the IC50 values for sulindac between AR (0.36 μM) and AKR1B10 (2.7 μM) might be explained by the different positioning and stacking interaction given by Phe122/Phe123, and by the presence of two buried and ordered water molecules in AKR1B10 but not in AR. Moreover, SAR analysis shows that the substitution of the sulfinyl group is structurally allowed in sulindac derivatives. Hence, sulindac and its derivatives emerge as lead compounds for the design of more potent and selective AR and AKR1B10 inhibitors.
Publication
Journal: Journal of Cancer
October/10/2019
Abstract
Overexpression of AKR1B10 correlated with tumorigenesis of many human malignancies; however, the prognostic value of AKR1B10 expression in patients with hepatocellular carcinoma (HCC) still remains controversial. In this analysis, AKR1B10 expression in HCC tumors were evaluated in GEO, TCGA and Oncomine databases, and a survival analysis of AKR1B10 based on TCGA profile was performed. We found that AKR1B10 was significantly overexpressed in tumors compared with nontumors in 7 GEO series (GSE14520, GSE25097, GSE33006, GSE45436, GSE55092, GSE60502, GSE77314) and TCGA profile (all P < 0.05). Meta-analysis in Oncomine database revealed that AKR1B10 was significantly upregulated in cirrhosis, liver cell dysplasia and HCC compared with normal tissues (all P < 0.05). Kaplan-Meier analysis demonstrated that high AKR1B10 in tumors were significantly associated with worse overall survival (OS) in HCC patients (P < 0.05). Subgroup analysis showed that AKR1B10 overexpression were associated with poor 1-year, 3-year and 5-year OS (all P < 0.05). In addition, prognostic values of AKR1B10 upregulation for OS were more significant in HCC with hepatitis-virus-free (P = 0.00055), White race (P = 0.0029) and alcohol-free (P = 0.013), and both in male and female (P = 0.014 and P = 0.034, respectively). In conclusion: AKR1B10 was upregulated in tumors and correlated with worse OS in HCC patients.
Publication
Journal: Pharmaceutics
February/22/2016
Abstract
Cytochrome P450 drug metabolizing enzymes are implicated in personalized medicine for two main reasons. First, inter-individual variability in CYP3A4 expression is a confounding factor during cancer treatment. Second, inhibition or induction of CYP3A4 can trigger adverse drug-drug interactions. However, inflammation can downregulate CYP3A4 and other drug metabolizing enzymes and lead to altered metabolism of drugs and essential vitamins and lipids. Little is known about effects of inflammation on expression of CYP450 genes controlling drug metabolism in the skin. Therefore, we analyzed seven published microarray datasets, and identified differentially-expressed genes in two inflammatory skin diseases (melanoma and psoriasis). We observed opposite patterns of expression of genes regulating metabolism of specific vitamins and lipids in psoriasis and melanoma samples. Thus, genes controlling the turnover of vitamin D (CYP27B1, CYP24A1), vitamin A (ALDH1A3, AKR1B10), and cholesterol (CYP7B1), were up-regulated in psoriasis, whereas melanomas showed downregulation of genes regulating turnover of vitamin A (AKR1C3), and cholesterol (CYP39A1). Genes controlling abnormal keratinocyte differentiation and epidermal barrier function (CYP4F22, SULT2B1) were up-regulated in psoriasis. The up-regulated CYP24A1, CYP4F22, SULT2B1, and CYP7B1 genes are potential drug targets in psoriatic skin. Both disease samples showed diminished drug metabolizing capacity due to downregulation of the CYP1B1 and CYP3A5 genes. However, melanomas showed greater loss of drug metabolizing capacity due to downregulation of the CYP3A4 gene.
Publication
Journal: Oncology Letters
January/18/2019
Abstract
Effective methods for predicting tumor response to preoperative chemotherapy are required. Aldo-ketoreductase family 1 member B10 (AKR1B10) is predominantly expressed in the gastrointestinal tract and serves an important function in cancer development and progression. The present study investigated whether AKR1B10 expression may predict the therapeutic response of locally advanced gastric cancer. A total of 53 patients with gastric cancer underwent neoadjuvant chemotherapy followed by surgery between January 2006 and December 2015. The protein expression level of AKR1B10 was determined in paraffin-embedded biopsy specimens using immunohistochemistry. Western blotting confirmed that the AKR1B10 protein is primarily localized to the cytoplasm. χ2 and Fisher's exact tests were used to determine the association of AKR1B10 with a number of clinic opathological features. Univariate and multivariate analyses were used to identify the prognostic factors. Survival rates were compared using Kaplan-Meier curves with a log-rank test. The positive rate of AKR1B10 protein expression was 58.5%, whereas 41.5% samples exhibited negative expression. The frequency of AKR1B10-positive gastric cancer samples was increased in patients with lymph node metastasis and decreased in those exhibiting tumor regression. The 5-years overall survival rate for the AKR1B10-positive group was significantly poorer than that for the AKR1B10-negative group. AKR1B10 expression was associated with lymph node metastasis and a poorer prognosis, along with a poor response to neoadjuvant chemotherapy suggesting that AKR1B10 may be a potential predictor for the therapeutic response of locally-advanced gastric cancer.
Publication
Journal: Journal of Oral Pathology and Medicine
June/25/2019
Abstract
Aldo-keto reductase family 1 member B10 (AKR1B10) is an enzyme implicated in physiological xenobiotic detoxification and also in pathological carcinogenesis. Overexpression of AKR1B10 has been reported in oral squamous cell carcinoma (OSCC), but its correlation with clinical prognosis is controversial. The aim of this study was to investigate and clarify the role of AKR1B10 in OSCC carcinogenesis.Tumor tissue specimens were surgically obtained from 107 patients with OSCC. The expression of AKR1B10 was analyzed by immunohistochemistry to explore the relationship between the level of AKR1B10 and clinicopathological features of OSCC patients. Kaplan-Meier survival and Cox proportional hazard analysis were used to determine the prognostic value of AKR1B10 in OSCC.High expression of AKR1B10 was found to be associated with tumor size (P = 0.043), perineural invasion (P = 0.012), and recurrence (P = 0.001) in OSCC. Cox model analysis revealed that high expression of AKR1B10 is significantly associated with poor overall and disease-free survival in OSCC patients. With the combination of clinicopathological factors in analysis, we found that the expression level of AKR1B10 was a practical indicator that could categorize OSCC patients into different risk groups. High expression of AKR1B10 was associated with a reduced survival in patients with well and moderately differentiated OSCC and even a high incidence of tumor recurrence in the patients with late-stage (III and IV) disease.We validated and expanded data on the expression of AKR1B10 in OSCC, suggesting that it is a valuable biomarker for prognostic prediction of recurrence and survival in OSCC.
Publication
Journal: Aging
July/2/2020
Abstract
Colorectal cancer (CRC) is a common malignancy worldwide with poor prognosis and survival rates. The aldo-keto reductase family 1 member B10 (AKR1B10) plays an important role in metabolism, cell proliferation and mobility, and is downregulated in CRC. We hypothesized that AKR1B10 would promote CRC genesis via a noncanonical oncogenic pathway and is a novel therapeutic target. In this study, AKR1B10 expression levels in 135 pairs of CRC and para-tumor tissues were examined, and its oncogenic role was determined using in vitro and in vivo functional assays following genetic manipulation of CRC cells. AKR1B10 was downregulated in CRC tissues compared to the adjacent normal colorectal tissues, and associated with the clinicopathological status of the patients. AKR1B10 depletion promoted the proliferation and migration of CRC cells in vitro, while its ectopic expression had the opposite effect. AKR1B10 was also significantly correlated with FGF1 gene and protein levels. Knockdown of AKR1B10 promoted tumor growth in vivo, and increased the expression of FGF1. Finally, AKR1B10 inhibited FGF1, and suppressed the proliferation and migration ability of CRC cells in an FGF1-dependent manner. In conclusion, AKR1B10 acts as a tumor suppressor in CRC by inactivating FGF1, and is a novel target for combination therapy of CRC.
Keywords: AKR1B10; FGF1; colorectal cancer; targeted therapy.
Publication
Journal: Carcinogenesis
July/6/2020
Abstract
AKR1B1 and AKR1B10, members of the aldo-keto reductase family of enzymes that participate in the polyol pathway of aldehyde metabolism, are aberrantly expressed in colon cancer. We previously showed that high expression of AKR1B1 (AKR1B1HIGH) was associated with enhanced motility, inflammation and poor clinical outcome in colon cancer patients. Using publicly available datasets and ex vivo gene expression analysis (n=51, Ankara cohort), we have validated our previous in silico finding that AKR1B1HIGH was associated with worse overall survival (OS) compared to patients with low expression of AKR1B1 (AKR1B1LOW) samples. A combined signature of AKR1B1HIGH and AKR1B10LOW was significantly associated with worse recurrence free survival in MSS patients and in patients with distal colon tumors as well as a higher mesenchymal signature when compared to AKR1B1LOW/AKR1B10HIGH tumors. When the patients were stratified according to Consensus Molecular Subtypes (CMS), AKR1B1HIGH/AKR1B10LOW samples were primarily classified as CMS4 with predominantly mesenchymal characteristics while AKR1B1LOW/AKR1B10HIGH samples were primarily classified as CMS3 which is associated with metabolic deregulation. Reverse Phase Protein Array (RPPA) carried out using protein samples from the Ankara cohort indicated that AKR1B1HIGH/AKR1B10LOW tumors showed aberrant activation of metabolic pathways. Western blot analysis of AKR1B1HIGH/AKR1B10LOW colon cancer cell lines also suggested aberrant activation of nutrient sensing pathways. Collectively, our data suggest that the AKR1B1HIGH/AKR1B10LOW signature may be predictive of poor prognosis, aberrant activation of metabolic pathways, and can be considered as a novel biomarker for colon cancer prognostication.
Keywords: AKR1B1; AKR1B10; CMS; EMT; biomarker; metabolism; prognosis.
Publication
Journal: Asian Pacific journal of cancer prevention : APJCP
December/2/2013
Abstract
BACKGROUND
Cigarette smoking is the major risk factor for development of lung cancer. Identification of effects of tobacco on airway gene expression may provide insight into the causes. This research aimed to compare gene expression of large airway epithelium cells in normal smokers (n=13) and non-smokers (n=9) in order to find genes which discriminate the two groups and assess cigarette smoking effects on large airway epithelium cells.
METHODS
Genes discriminating smokers from non-smokers were identified by applying a neural network clustering method, growing self-organizing maps (GSOM), to microarray data according to class discrimination scores. An index was computed based on differentiation between each mean of gene expression in the two groups. This clustering approach provided the possibility of comparing thousands of genes simultaneously.
RESULTS
The applied approach compared the mean of 7,129 genes in smokers and non-smokers simultaneously and classified the genes of large airway epithelium cells which had differently expressed in smokers comparing with non-smokers. Seven genes were identified which had the highest different expression in smokers compared with the non-smokers group: NQO1, H19, ALDH3A1, AKR1C1, ABHD2, GPX2 and ADH7. Most (NQO1, ALDH3A1, AKR1C1, H19 and GPX2) are known to be clinically notable in lung cancer studies. Furthermore, statistical discriminate analysis showed that these genes could classify samples in smokers and non-smokers correctly with 100% accuracy. With the performed GSOM map, other nodes with high average discriminate scores included genes with alterations strongly related to the lung cancer such as AKR1C3, CYP1B1, UCHL1 and AKR1B10.
CONCLUSIONS
This clustering by comparing expression of thousands of genes at the same time revealed alteration in normal smokers. Most of the identified genes were strongly relevant to lung cancer in the existing literature. The genes may be utilized to identify smokers with increased risk for lung cancer. A large sample study is now recommended to determine relations between the genes ABHD2 and ADH7 and smoking.
Publication
Journal: Scientific Reports
July/22/2017
Abstract
Global prevalence of breast cancer and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of field based 3D-QSAR model based on human breast cancer cell line MCF7 in vitro anticancer activity, which defines the molecular level understanding and regions of structure-activity relationship for triterpene maslinic acid and its analogs. The key features such as average shape, hydrophobic regions and electrostatic patterns of active compounds were mined and mapped to virtually screen potential analogs. Then, field points based descriptors were used to develop a 3D-QSAR model by aligning known active compounds onto identified pharmacophore template. The derived LOO validated PLS regression QSAR model showed acceptable r2 0.92 and q2 0.75. After screening through Lipinski's rule of five filter for oral bioavailability, ADMET risk filter for drug like features, and synthetic accessibility for chemical synthesis, out of 593 hits, 39 were left top hits. Docking screening was performed through identified potential targets namely, AKR1B10, NR3C1, PTGS2, and HER2. Finally, compound P-902 was identified as best hit. This study, would be of great help in lead identification and optimization for early drug discovery.
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Publication
Journal: Acta Pharmacologica Sinica
July/21/2016
Abstract
OBJECTIVE
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.
CONCLUSIONS
Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors.
Publication
Journal: Gene
March/18/2020
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease and associated with a wide spectrum of hepatic disorders ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). NASH is projected to become the most common indication for liver transplantation, and the annual incidence rate of NASH-related HCC is 5.29 cases per 1000 person-years. Owing to the epidemics of NAFLD and the unclear mechanism of NAFLD progression, it is important to elucidate the underlying NAFLD mechanisms in detail. NASH is mainly caused by the development of NAFL Therefore, it is also of great significance to understand the mechanism of progression from NAFL to NASH. Gene expression chip data for NAFLD and NASH were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) between NAFLD and normal controls (called DEGs for NAFLD), as well as between NASH and normal tissue (called DEGs for NASH-Normal),and between NASH and NAFL tissue (called DEGs for NASH-NAFL). For DEGs for the NAFLD group, key genes were identified by studying the form of intersection. Potential functions of DEGs for NASH were then analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A protein-protein interaction network (PPI) was constructed using the STRING database. A total of 249 DEGs and one key gene for NAFLD were identified. For NASH-Normal, 514 DEGs and 11 hub genes were identified, three of which were closely related to the survival analysis of HCC, and potentially closely related to progression from NASH to HCC. One key gene for NASH-NAFL (AKR1B10) was identified. These genes appear to mediate the molecular mechanism underlying NAFLD and may be promising biomarkers for the presence of NASH.
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