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Genome Medicine Aug 2022Lung cancer, one of the most common malignant tumors, exhibits high inter- and intra-tumor heterogeneity which contributes significantly to treatment resistance and...
BACKGROUND
Lung cancer, one of the most common malignant tumors, exhibits high inter- and intra-tumor heterogeneity which contributes significantly to treatment resistance and failure. Single-cell RNA sequencing (scRNA-seq) has been widely used to dissect the cellular composition and characterize the molecular properties of cancer cells and their tumor microenvironment in lung cancer. However, the transcriptomic heterogeneity among various cancer cells in non-small cell lung cancer (NSCLC) warrants further illustration.
METHODS
To comprehensively analyze the molecular heterogeneity of NSCLC, we performed high-precision single-cell RNA-seq analyses on 7364 individual cells from tumor tissues and matched normal tissues from 19 primary lung cancer patients and 1 pulmonary chondroid hamartoma patient.
RESULTS
In 6 of 16 patients sequenced, we identified a significant proportion of cancer cells simultaneously expressing classical marker genes for two or even three histologic subtypes of NSCLC-adenocarcinoma (ADC), squamous cell carcinoma (SCC), and neuroendocrine tumor (NET) in the same individual cell, which we defined as mixed-lineage tumor cells; this was verified by both co-immunostaining and RNA in situ hybridization. These data suggest that mixed-lineage tumor cells are highly plastic with mixed features of different types of NSCLC. Both copy number variation (CNV) patterns and mitochondrial mutations clearly showed that the mixed-lineage and single-lineage tumor cells from the same patient had common tumor ancestors rather than different origins. Moreover, we revealed that patients with high mixed-lineage features of different cancer subtypes had worse survival than patients with low mixed-lineage features, indicating that mixed-lineage tumor features were associated with poorer prognosis. In addition, gene signatures specific to mixed-lineage tumor cells were identified, including AKR1B1. Gene knockdown and small molecule inhibition of AKR1B1 can significantly decrease cell proliferation and promote cell apoptosis, suggesting that AKR1B1 plays an important role in tumorigenesis and can serve as a candidate target for tumor therapy of NSCLC patients with mixed-lineage tumor features.
CONCLUSIONS
In summary, our work provides novel insights into the tumor heterogeneity of NSCLC in terms of the identification of prevalent mixed-lineage subpopulations of cancer cells with combined signatures of SCC, ADC, and NET and offers clues for potential treatment strategies in these patients.
Topics: Adenocarcinoma; Aldehyde Reductase; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Prognosis; RNA-Seq; Tumor Microenvironment
PubMed: 35962452
DOI: 10.1186/s13073-022-01089-9 -
International Journal of Molecular... Feb 2022NAD(H)/NADP(H)-dependent aldehyde/alcohol oxidoreductase (AAOR) participates in a wide range of physiologically important cellular processes by reducing aldehydes or...
NAD(H)/NADP(H)-dependent aldehyde/alcohol oxidoreductase (AAOR) participates in a wide range of physiologically important cellular processes by reducing aldehydes or oxidizing alcohols. Among AAOR substrates, furan aldehyde is highly toxic to microorganisms. To counteract the toxic effect of furan aldehyde, some bacteria have evolved AAOR that converts furan aldehyde into a less toxic alcohol. Based on biochemical and structural analyses, we identified YugJ as an atypical AAOR that reduces furan aldehyde. YugJ displayed high substrate specificity toward 5-hydroxymethylfurfural (HMF), a furan aldehyde, in an NADPH- and Ni-dependent manner. YugJ folds into a two-domain structure consisting of a Rossmann-like domain and an α-helical domain. YugJ interacts with NADP and Ni using the interdomain cleft of YugJ. A comparative analysis of three YugJ structures indicated that NADP(H) binding plays a key role in modulating the interdomain dynamics of YugJ. Noticeably, a nitrate ion was found in proximity to the nicotinamide ring of NADP in the YugJ structure, and the HMF-reducing activity of YugJ was inhibited by nitrate, providing insights into the substrate-binding mode of YugJ. These findings contribute to the characterization of the YugJ-mediated furan aldehyde reduction mechanism and to the rational design of improved furan aldehyde reductases for the biofuel industry.
Topics: Aldehyde Reductase; Bacillus subtilis; Bacterial Proteins; Cloning, Molecular; Crystallography, X-Ray; Furaldehyde; Models, Molecular; NADP; Nickel; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Substrate Specificity
PubMed: 35163804
DOI: 10.3390/ijms23031882 -
Journal of Enzyme Inhibition and... Dec 2020The ability to catalyse a reaction acting on different substrates, known as "broad-specificity" or "multi-specificity", and to catalyse different reactions at the same... (Review)
Review
The ability to catalyse a reaction acting on different substrates, known as "broad-specificity" or "multi-specificity", and to catalyse different reactions at the same active site ("promiscuity") are common features among the enzymes. These properties appear to go against the concept of extreme specificity of the catalytic action of enzymes and have been re-evaluated in terms of evolution and metabolic adaptation. This paper examines the potential usefulness of a differential inhibitory action in the study of the susceptibility to inhibition of multi-specific or promiscuous enzymes acting on different substrates. Aldose reductase is a multi-specific enzyme that catalyses the reduction of both aldoses and hydrophobic cytotoxic aldehydes and is used here as a concrete case to deal with the differential inhibition approach.
Topics: Aldehyde Reductase; Aldehydes; Biocatalysis; Enzyme Inhibitors; Humans
PubMed: 32208768
DOI: 10.1080/14756366.2020.1743988 -
Pharmacological Reviews Jul 2021Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to alcohols for conjugation reactions to proceed. They are implicated in... (Review)
Review
Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are directly involved in their metabolism or help eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid peroxides). Furthermore, this cellular stress activates the Nuclear factor-erythroid 2 p45-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human genes are upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines, mitomycin, platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the elimination of progestogens and are involved in hormonal-dependent malignancies. They are upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance. Inhibitors of the NRF2 system or pan-AKR1C inhibitors offer promise to surmount cancer drug resistance and/or synergize the effects of existing drugs. SIGNIFICANCE STATEMENT: Aldo-keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR pan-inhibitors to improve clinical outcome.
Topics: Aldehyde Reductase; Aldo-Keto Reductases; Antineoplastic Agents; Drug Resistance; Humans; Neoplasms
PubMed: 34312303
DOI: 10.1124/pharmrev.120.000122 -
Cell Reports. Medicine Jun 2023Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol...
Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.
Topics: Animals; Zebrafish; Glycosylation; Aldehyde Reductase; Mannose; Metabolomics
PubMed: 37257447
DOI: 10.1016/j.xcrm.2023.101056 -
Mini Reviews in Medicinal Chemistry Apr 2012Nanotechnology is a rapidly emerging drug-delivery system that makes possible the controlled release of small molecules, and nanodelivery of therapeutic molecules using... (Review)
Review
Nanotechnology is a rapidly emerging drug-delivery system that makes possible the controlled release of small molecules, and nanodelivery of therapeutic molecules using nanoparticles or nanogels represents a major improvement for more focused delivery of such therapeutic molecules. The delivery of insulin for the control of diabetes mellitus (DM) and aldose reductase inhibitor (ARI) for diabetic complications may provide better treatment of diabetes. A structural overview of aldose reductase including computational docking experiments with HAR-1, various ARIs, aldose-keto reductase, and nanodelivery of insulin, ARI's, and drug molecules are described.
Topics: Aldehyde Reductase; Animals; Diabetes Mellitus; Drug Carriers; Enzyme Inhibitors; Humans; Hypoglycemic Agents; Nanostructures
PubMed: 22303947
DOI: 10.2174/138955712799829294 -
International Journal of Molecular... Jan 2021Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the... (Review)
Review
Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.
Topics: Aldehyde Reductase; Animals; Diabetes Mellitus; Enzyme Inhibitors; Glucose; Humans; Metabolic Networks and Pathways; Oxidation-Reduction; Polymers; Schwann Cells; Sorbitol
PubMed: 33494154
DOI: 10.3390/ijms22031031 -
Metabolic Engineering Sep 2014Advances in synthetic biology and metabolic engineering have enabled the construction of novel biological routes to valuable chemicals using suitable microbial hosts....
Advances in synthetic biology and metabolic engineering have enabled the construction of novel biological routes to valuable chemicals using suitable microbial hosts. Aldehydes serve as chemical feedstocks in the synthesis of rubbers, plastics, and other larger molecules. Microbial production of alkanes is dependent on the formation of a fatty aldehyde intermediate which is converted to an alkane by an aldehyde deformylating oxygenase (ADO). However, microbial hosts such as Escherichia coli are plagued by many highly active endogenous aldehyde reductases (ALRs) that convert aldehydes to alcohols, which greatly complicates strain engineering for aldehyde and alkane production. It has been shown that the endogenous ALR activity outcompetes the ADO enzyme for fatty aldehyde substrate. The large degree of ALR redundancy coupled with an incomplete database of ALRs represents a significant obstacle in engineering E. coli for either aldehyde or alkane production. In this study, we identified 44 ALR candidates encoded in the E. coli genome using bioinformatics tools, and undertook a comprehensive screening by measuring the ability of these enzymes to produce isobutanol. From the pool of 44 candidates, we found five new ALRs using this screening method (YahK, DkgA, GldA, YbbO, and YghA). Combined deletions of all 13 known ALRs resulted in a 90-99% reduction in endogenous ALR activity for a wide range of aldehyde substrates (C2-C12). Elucidation of the ALRs found in E. coli could guide one in reducing competing alcohol formation during alkane or aldehyde production.
Topics: Aldehyde Reductase; Aldehydes; Alkanes; Enzyme Activation; Escherichia coli; Escherichia coli Proteins; Gene Silencing; Genetic Enhancement; Metabolic Engineering; Signal Transduction
PubMed: 25108218
DOI: 10.1016/j.ymben.2014.07.012 -
Cardiovascular & Hematological Agents... Sep 2012Cardiovascular disease represents the major cause of morbidity and mortality in patients with diabetes mellitus. Studies by us and others have implicated increased flux... (Review)
Review
Cardiovascular disease represents the major cause of morbidity and mortality in patients with diabetes mellitus. Studies by us and others have implicated increased flux via aldose reductase (AR) as a key player in mediating diabetic complications, including cardiovascular complications. Data suggest that increased flux via AR in diabetics perpetuates increased injury after myocardial infarction, accelerates atherosclerotic lesion formation, and promotes restenosis via multiple mechanisms. Most importantly, studies have shown that increased generation of reactive oxygen species due to flux via AR has been a common feature in animal models of diabetic cardiovascular disease. Taken together, these considerations place AR in the center of biochemical and molecular stresses that characterize the cardiovascular complications of diabetes. Stopping AR-dependent signaling may hold the key to interrupting cycles of cellular perturbation and tissue damage in diabetic cardiovascular complications.
Topics: Aldehyde Reductase; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Oxidative Stress
PubMed: 22632267
DOI: 10.2174/187152512802651097 -
Kidney International. Supplement Sep 2000BACKGROUND; In diabetic renal complications, hyperglycemia may cause damage at a cellular level in both glomerular and tubular locations, often preceding overt... (Review)
Review
UNLABELLED
BACKGROUND; In diabetic renal complications, hyperglycemia may cause damage at a cellular level in both glomerular and tubular locations, often preceding overt dysfunction. Our previous work has implicated aldose reductase in a pathway whereby aldose reductase-induced use of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) drives the pentose phosphate pathway, which culminates in a protein kinase C-induced increase in glomerular prostaglandin production and loss of mesangial cell contractility as a possible cause of hyperfiltration and glomerular dysfunction in diabetes. In this model, aldose reductase inhibition in vitro redresses all aspects of the pathway proposed to lead to hyperfiltration; aldose reductase inhibition in vivo gives only a partial amelioration over the short-term or is without effect in the longer term on microalbuminuria, which follows glomerular and tubular dysfunction. In diabetes, hyperglycemia-induced renal polyol pathway activity does not occur in isolation but instead in tandem with oxidative changes and the production of reactive dicarbonyls and alpha,beta-unsaturated aldehydes. Aldose reductase may detoxify these compounds. We investigated this aspect in a transgenic rat model with human aldose reductase cDNA under the control of the cytomegalovirus promoter with tubular expression of transgene.
METHODS
Tubules (S3 region-enriched) from transgenic and control animals were prepared, exposed to oxidative stress, and analyzed to determine the cellular protein dicarbonyl content.
RESULTS
In tubules from transgenic animals, oxidative stress-induced dicarbonyls were significantly reduced, an effect not seen when an aldose reductase inhibitor was present.
CONCLUSIONS
Aldose reductase may both exacerbate and alleviate the production of metabolites that lead to hyperglycemia-induced cellular impairment, with the balance determining the extent of dysfunction.
Topics: Aldehyde Reductase; Animals; Diabetic Nephropathies; Diglycerides; Free Radicals; Glucose; Glycosylation; Humans; Kidney Tubules; Oxidative Stress; Polymers; Rats
PubMed: 10997684
DOI: 10.1046/j.1523-1755.2000.07702.x