Engineering aldo-keto reductase 1B10 to mimic the distinct 1B15 topology and specificity towards inhibitors and substrates, including retinoids and steroids

Gimenez-Dejoz, Joan; Weber, Susanne; Fernández-Pardo, Álvaro; Möller, Gabriele; Adamski, Jerzy; Porté, Sergio; Parés, Xavier; Farrés, Jaume

doi:10.1016/j.cbi.2019.04.030

Cited by 11 publications

(8 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 [ 2 , 3 ]. The three AKRs are NADPH-dependent reductases and display overlapping substrate specificities for aromatic and aliphatic aldehydes but differ in their catalytic efficiencies [ 2 , 3 , 4 , 5 , 6 ], which is notably higher for retinal (all- trans -retinaldehyde) in AKR1B10 [ 5 ]. In addition, the glucose reductase activity characteristics of AKR1B1 are very low for AKR1B10 and AKR1B15 [ 2 , 4 , 5 ], and prostaglandin F synthase activity is observed with AKR1B1, but not with AKR1B10 [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the glucose reductase activity characteristics of AKR1B1 are very low for AKR1B10 and AKR1B15 [ 2 , 4 , 5 ], and prostaglandin F synthase activity is observed with AKR1B1, but not with AKR1B10 [ 7 ]. In contrast to AKR1B1, AKR1B10 and AKR1B15 exhibit low 17β-hydroxysteroid dehydrogenase activity for estrone and 4-androstene-3,17-dione [ 3 , 6 ]. For subcellular localization, AKR1B1 and AKR1B10 are cytosolic, whereas AKR1B15 is in the mitochondria [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Role of AKR1B10 in Physiology and Pathophysiology

2021

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of AKR1B10 in Physiology and Pathophysiology

2021

View full text Add to dashboard Cite

show abstract

“…Among them, studies have shown that PRKY only plays an important role in the male reproductive system, 38 and AKR1B15 has a unique effect on the higher activity of steroids and ketones. 39 Subsequently, we found that compared with the low-risk group, patients in the highrisk group had a worse prognosis and higher sensitivity to cisplatin, docetaxel, camptothecin, and paclitaxel. Analysis of the ROC curve and nomogram showed that the model had greater prognostic accuracy at 1, 3, and 5 years.…”

Section: Discussionmentioning

confidence: 96%

Gender dimorphism in survival of patients with lymph node metastasis of bladder cancer

et al. 2022

View full text Add to dashboard Cite

Background: The effect of gender on the prognosis of bladder cancer (BCa) in different metastatic sites is insufficiently understood. We aimed to assess the impact and potential mechanisms of a combination of gender dimorphism and BCa metastasis sites on the risk of death. Methods: Independent predictors of overall survival and cancer-specific survival were analyzed after stratification by gender and metastasis sites from the Surveillance, Epidemiology, and End Results database. Furthermore, gender-differentially expressed genes (DEGs) and function-enriched annotations for patients with lymph node metastasis (LNM) were identified from The Cancer Genome Atlas (TCGA) database. A gender-associated signature was constructed in TCGA and validated in the IMvigor210 trial, and the magnetic resonance imaging-based radiomics signature was developed in our center to predict the gender-associated signature. Results: In patients with metastatic BCa, the most common site of metastasis is bone in men and lung in women. Moreover, stratified by sex, LNM had a better prognosis in men than visceral metastasis, which was not observed in female. Similarly, stratified by the metastasis site, the prognosis of men in patients with LNM is better than that of women, which was not observed in visceral metastasis patients. Enrichment of DEGs between sexes in patients with LNM may be related to metastasis and tumor immunity, especially the role of neutrophils. Moreover, the gender-associated signature is related to the clinicopathological characteristics of patients, and patients in the high-risk group had worse survival outcomes, and higher susceptibility to cisplatin, docetaxel, camptothecin, and paclitaxel. A nomogram combined with the signature and clinical staging showed significant predictive power in survival prediction. Furthermore, patients with high radiomics scores had a strong tendency for high-risk group. Conclusion: These results may improve the understanding of the differences in tumor biology between sexes and thus provide additional evidence for individualized treatment in BCa.

show abstract

“…The decrease in optical density at 340 nm is monitored for 20 min at 37℃ in a microplate reader (BioTek Instruments Inc., Winooski, VT, USA) at 340 nm. One unit (U) of enzyme activity was defined as the amount of enzyme that catalyzes the oxidation of 1 μM NADPH per minute at 37 °C [13].…”

Section: Akr1b10 Enzyme Activity Assaymentioning

confidence: 99%

AKR1B10 Inhibitor Epalrestat Facilitates Sorafenib-Induced Apoptosis and Autophagy Via Targeting the mTOR Pathway in Hepatocellular Carcinoma

Geng¹,

Jin²,

Li³

et al. 2020

Int. J. Med. Sci.

View full text Add to dashboard Cite

Sorafenib is the standard systemic treatment for advanced hepatocellular carcinoma (HCC), and improving its therapeutic effects is crucial for addressing cancer aggression. We previously reported that epalrestat, an aldo-keto reductase 1B10 inhibitor, enhanced sorafenib's inhibitory effects on HCC xenograft in nude mice. This study aimed to elucidate the mechanism of epalrestat's anti-tumour enhancing effects on sorafenib. HepG2 cells were treated with sorafenib, epalrestat, and their combination. Cell proliferation was assessed with Cell Counting Kit-8 and colony formation assays. AKR1B10 supernate concentration and enzyme activity were detected by ELISA assay and the decrease of optical density of NADPH at 340 nm. Cell cycle and apoptosis analyses were performed with flow cytometry. Western blots clarified the molecular mechanism underlying effects on cell cycle, apoptosis, and autophagy. The anti-tumour mechanism was then validated in vivo through TUNEL and immunohistochemistry staining of HCC xenograft sections. Epalrestat combined with sorafenib inhibited HepG2 cellular proliferation in vitro, arrested the cell cycle at G0/G1, and promoted apoptosis and autophagy. Treatment with a specific mTOR activator MHY-1485 increased mTOR phosphorylation, while suppressing apoptosis and autophagy. Consistent with in vitro results, data from the HCC-xenograft nude mouse model also indicated that combined treatment inhibited the mTOR pathway and promoted apoptosis and autophagy. In conclusion, epalrestat heightens sorafenib's anti-cancer effects via blocking the mTOR pathway, thus inducing cell cycle arrest, apoptosis, and autophagy.

show abstract

Engineering aldo-keto reductase 1B10 to mimic the distinct 1B15 topology and specificity towards inhibitors and substrates, including retinoids and steroids

Cited by 11 publications

References 53 publications

The Role of AKR1B10 in Physiology and Pathophysiology

The Role of AKR1B10 in Physiology and Pathophysiology

Gender dimorphism in survival of patients with lymph node metastasis of bladder cancer

AKR1B10 Inhibitor Epalrestat Facilitates Sorafenib-Induced Apoptosis and Autophagy Via Targeting the mTOR Pathway in Hepatocellular Carcinoma

Contact Info

Product

Resources

About