Omeprazole as a potent activator of human cytosolic aldehyde dehydrogenase ALDH1A1

Calleja, Luis Francisco; Belmont-Díaz, Javier A.; Medina-Contreras, Óscar; Quezada, Héctor; Yoval-Sánchez, Belem; Campos-Garcı́a, Jesús; Rodríguez‐Zavala, José S.

doi:10.1016/j.bbagen.2019.129451

Cited by 12 publications

(13 citation statements)

References 38 publications

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“…One of the most significant losses in response to glycolytic impairment in both KO clones was the concomitant repression of several aldehyde dehydrogenase transcripts, specifically ALDH1A1, ALDH2 (mitochondrial), and ALDH3A1, which could create a non-ergogenic vulnerability to cancer cells. High expression of these genes is observed in many cancers, playing a critical role in the biosynthesis of retinoic acid (RA), nuclear signaling (48,49) and contribution toward the "stemness" or self-renewal features which perpetuates tumor initiation and drug/radiation resistance (50)(51)(52)(53)(54). While ALDHs are keys in the collective stemness gene profile (CSN6, CD15, CD24, CD166, TRIM21, CD133, CD82, CD105, CD44, CD90, ALDH1A1, EPCAM, SOX2, SOX9, LGR5, BMI1, NANOG, OCT4, CXCR4 and CD24), ALDHs are specifically up-regulated by pro-oncogenic proteins such as cytokines, growth factors or pollutants which trigger epithelial-mesenchymal transition (EMT), colony formation, migration, and metastasis in diverse cancers with poor clinical outcome (55-61).…”

Section: Reduction In Aldehyde Dehydrogenase Transcripts (Aldhs)mentioning

confidence: 99%

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Mazzio

Badisa

Mack

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Nearly all mammalian tumors of diverse tissues are believed to be dependent on fermentative glycolysis, marked by elevated production of lactic acid and expression of glycolytic enzymes, most notably lactic acid dehydrogenase (LDH). Therefore, there has been significant interest in developing chemotherapy drugs that selectively target various isoforms of the LDH enzyme. However, considerable questions remain as to the consequences of biological ablation of LDH or upstream targeting of the glycolytic pathway. Materials and Methods: In this study, we explore the biochemical and whole transcriptomic effects of CRISPR-Cas9 gene knockout (KO) of lactate dehydrogenases A and B [LDHA/B double KO (DKO)] and glucose-6-phosphate isomerase (GPI KO) in the human colon cancer cell line LS174T, using Affymetrix 2.1 ST arrays. Results: The metabolic biochemical profiles corroborate that relative to wild type (WT), LDHA/B DKO produced no lactic acid, (GPI KO) produced minimal lactic acid and both KOs displayed higher mitochondrial respiration, and minimal use of glucose with no loss of cell viability. These findings show a high biochemical energy efficiency as measured by ATP in glycolysis-null cells. Next, transcriptomic analysis conducted on 48,226 mRNA transcripts reflect 273 differentially expressed genes (DEGS) in the GPI KO clone set, 193 DEGS in the LDHA/B DKO clone set with 47 DEGs common to both KO clones. Glycolytic-null cells reflect up-regulation in gene transcripts typically associated with nutrient deprivation / fasting and possible use of fats for energy: thioredoxin interacting protein (TXNIP), mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), PPARγ coactivator 1α (PGC-1α), and acetyl-CoA acyltransferase 2 (ACAA2). Other changes in non-ergometric transcripts in both KOs show losses in "stemness", WNT signaling pathway, chemo/radiation resistance, retinoic acid synthesis, drug detoxification, androgen/estrogen activation, and extracellular matrix reprogramming genes. Conclusion: These findings demonstrate that: 1) The "Warburg effect" is dispensable, 2) loss of the LDHAB gene is not only inconsequential to viability but fosters greater mitochondrial energy, and 3) drugs that target LDHA/B are likely to be ineffective without a plausible combination second drug target. Common features across diverse mammalian tumors include the rapid glycolytic activity, greater expression of lactate dehydrogenases (LDH) and subsequent overproduction of lactic acid, occurring regardless of the presence of oxygen (Warburg effect) (1,2). This unique trait of cancer has been studied for decades, where researchers have geared off original focus from its role in metabolism to its role in acidification of the tumor microenvironment (TME), a formidable driving force for tumor growth, metastasis, aggressiveness, chemo/radiation resistance and loss of immune surveillance (3-8). This loss of immune surveillance 469 This article is freely accessible online.

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Section: Reduction In Aldehyde Dehydrogenase Transcripts (Aldhs)mentioning

confidence: 99%

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Mazzio

Badisa

Mack

et al. 2020

Cancer Genomics Proteomics

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“…1C). Additional experiments were conducted to determine the optimum concentration of omeprazole to incubate the cells and the exposure time to light, since it was previously determined that omeprazole requires light and the presence of the coenzyme to be activated in the active site of ALDH1A1 [17]. It was proposed that NAD + (or NADH) is required to activate the catalytic cysteine by diminishing its pKa value, while light is needed to activate the benzimidazole ring of omeprazole, which abstracts the proton from the sulfhydryl group of the catalytic cysteine, previously activated by coenzyme binding.…”

Section: Resultsmentioning

confidence: 99%

“…ALDH1A1 and ALDH2 are susceptible to inactivation by acrolein, 2-hexenal, 2nonenal, and 4-HNE [8,9,14]. This inactivation is prevented when the enzymes are incubated with their activators, ALDH2 with Alda-1 and ALDH1A1 with Alda-1, tamoxifen, or omeprazole [15][16][17]. ALDH1A1 is present in the cytosol of cells and is responsible for the detoxification of aldehydes generated outside the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

“…In a previous work, we reported that omeprazole, a stomach proton‐pump inhibitor, increases four‐ to sixfold the activity of human recombinant ALDH1A1 in vitro , enhancing the catalytic efficiency of the enzyme [17]. However, for successful activation, besides incubation with omeprazole, the enzyme required the presence of the coenzyme and exposure to light of 310 nm [17]. To evaluate whether the activation of ALDH1A1 was able to protect cells from oxidative stress in that work, Escherichia coli cells expressing the human enzyme were used.…”

Section: Introductionmentioning

confidence: 99%

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Activation of ALDH1A1 by omeprazole reduces cell oxidative stress damage

Calleja¹,

Yoval-Sánchez²,

Hernández‐Esquivel³

et al. 2021

The FEBS Journal

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Under physiological conditions, cells produce low basal levels of reactive oxygen species (ROS); however, in pathologic conditions ROS production increases dramatically, generating high concentrations of toxic unsaturated aldehydes. Aldehyde dehydrogenases (ALDHs) are responsible for detoxification of these aldehydes protecting the cell. Due to the physiological relevance of these enzymes, it is important to design strategies to modulate their activity. It was previously reported that omeprazole activation of ALDH1A1 protected Escherichia coli cells overexpressing this enzyme, from oxidative stress generated by H 2 O 2 . In this work, omeprazole cell protection potential was evaluated in eukaryotic cells. AS-30D cell or hepatocyte suspensions were subjected to a treatment with omeprazole and exposure to light (that is required to activate omeprazole in the active site of ALDH) and then exposed to H 2 O 2 . Cells showed viability similar to control cells, total activity of ALDH was preserved, while cell levels of lipid aldehydes and oxidative stress markers were maintained low. Cell protection by omeprazole was avoided by inhibition of ALDHs with disulfiram, revealing the key role of these enzymes in the protection. Additionally, omeprazole also preserved ALDH2 (mitochondrial isoform) activity, diminishing lipid aldehyde levels and oxidative stress in this organelle, protecting mitochondrial respiration and transmembrane potential formation capacity, from the stress generated by H 2 O 2 . These results highlight the important role of ALDHs as part of the antioxidant system of the cell, since if the activity of these enzymes decreases under stress conditions, the viability of the cell is compromised.

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“…The authors calculated the binding energy of the five ligands and were able to identify the highest binding affinity with GB2, a component of Garcinia kolaviron, to the enzyme. Further, L. F. Calleja, et al performed a docking analysis, via the UCSF Chimera package 1.5.2., to test ALDH1A1's interaction with a potential inhibitor, which showed that two potential orientations exist for omeprazole in the ALDH active site 12,13 . This study also reinforced the positive effect of using a large variety of substituents to calculate the activity within the active site.…”

Section: Introductionmentioning

confidence: 99%

The effects of ligand charge, orientation and size on the binding of potential inhibitors for aldehyde dehydrogenase

Magee

Peterson

Cafiero

et al. 2020

Computational and Theoretical Chemistry

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L-DOPA, used as a therapy for patients with Parkinson's disease, is transformed into needed dopamine in the brain. This dopamine can then be deactivated via metabolism by a series of enzymes, including aldehyde dehydrogenase (ALDH). The targeted inhibition of the ALDH enzyme may help to prolong L-DOPA therapy. A series of potential inhibitors has been studied via ab initio models using a crystalstructure of the ALDH enzyme with an inhibitor bound in its active site (PDB ID: 4WP7). The positions of novel dopaminergic derivatives were optimized in the active site using M062X/6-31G with implicit solvation and relaxed amino-acid side-chains. This work examines different single molecule orientations, as well as double molecule configurations. Various sizes of ligands were also studied. Interaction energies between the ligands and the protein were calculated using M062X with the 6-311+G* basis set. Some potential inhibitors show promising results such as the MP and CAM series.

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Omeprazole as a potent activator of human cytosolic aldehyde dehydrogenase ALDH1A1

Cited by 12 publications

References 38 publications

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

Activation of ALDH1A1 by omeprazole reduces cell oxidative stress damage

The effects of ligand charge, orientation and size on the binding of potential inhibitors for aldehyde dehydrogenase

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