Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA<sub>1</sub> and Clinically Used Prostaglandins

Díez-Dacal, Beatriz; Sánchez‐Gómez, Francisco J.; Sánchez‐Murcia, Pedro A.; Milackova, Ivana; Zimmerman, Tahl; Ballekova, Jana; García‐Martín, Elena; Agúndez, José A. G.; Gharbi, Severine; Gago, Federico; Štefek, Milan

doi:10.1124/mol.115.100693

Cited by 17 publications

(16 citation statements)

References 57 publications

(59 reference statements)

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“… 24 More recently, other potential clinical uses of PGA 1 or its analogs have been explored, including the potential beneficial effects of A-type cyclopentenone prostaglandins in atherosclerosis 44 and its potential use in the inhibition of the aldo-keto reductase enzymes, which are involved in cancer resistance to chemical treatment and in the development of diabetic complications. 45 , 46 Here our data highlight the possibility that cyclopentenone prostaglandins, because of their specific cellular effects, can be useful in the design of new therapeutic drugs and these studies are under way.…”

Section: Discussionmentioning

confidence: 70%

PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

et al. 2016

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The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment.

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Section: Discussionmentioning

confidence: 70%

PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

et al. 2016

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“…Increased aldose reductase activity is a well‐established pathogenic factor for several diseases, for which it is considered a crucial drug target (Díez‐Dacal et al., ). Accumulating evidence indicates that it plays a complex role in inflammation (Sánchez‐Gómez et al., ; Srivastava et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…However, processing of high levels of reactive species could lead to generation of proinflammatory metabolites and/or depletion of antioxidant defenses, for which a positive inflammatory feedback may occur (Ramana et al., ). Remarkably, AKR1B1 itself is a target for covalent modification by electrophilic species, which can stimulate or inhibit its activity depending on the modifying moiety (Díez‐Dacal et al., ; Srivastava et al., ). Therefore, understanding the involvement of AKR1B1 in a particular pathology requires detailed consideration of the multiple factors involved.…”

Section: Discussionmentioning

confidence: 99%

Asthma and allergic rhinitis associate with the rs2229542 variant that induces a p.Lys90Glu mutation and compromises AKR1B1 protein levels

et al. 2018

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Asthma and rhinitis are two of the main clinical manifestations of allergy, in which increased reactive oxygen or electrophilic species can play a pathogenic role. Aldose reductase (AKR1B1) is involved in aldehyde detoxification and redox balance. Recent evidence from animal models points to a role of AKR1B1 in asthma and rhinitis, but its involvement in human allergy has not been addressed. Here, the putative association of allergic rhinitis and asthma with AKR1B1 variants has been explored by analysis of single-strand variants on the AKR1B1 gene sequence in 526 healthy subjects and 515 patients with allergic rhinitis, 366 of whom also had asthma. We found that the rs2229542 variant, introducing the p.Lys90Glu mutation, was significantly more frequent in allergic patients than in healthy subjects. Additionally, in cells transfected with expression vectors carrying the wild-type or the p.Lys90Glu variant of AKR1B1, the mutant consistently attained lower protein levels than the wild-type and showed a compromised thermal stability. Taken together, our results show that the rs2229542 variant associates with asthma and rhinitis, and hampers AKR1B1 protein levels and stability. This unveils a connection between the genetic variability of aldose reductase and allergic processes.

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“…MS approaches exist that allow detection of non-covalent drug protein complexes. In the case of the enzyme aldose reductase, a complex with non-electrophilic prostaglandins that is reversed under denaturing conditions has been observed by MALDI-TOF MS [52]. This type of interaction can affect the function and conformation of the proteins and/or shield specific sites for modification by other drugs or endogenous mediators.…”

Section: Non-covalent Drug-protein Interactionsmentioning

confidence: 99%

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

González-Morena¹,

Montanez²,

Aldini³

et al. 2017

CPD

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Drug hypersensitivity reactions result from the activation of the immune system by drugs or their metabolites. The clinical presentations of drug hypersensitivity can range from relatively mild local manifestations to severe systemic syndromes that can be life-threatening. As in other allergic reactions, the causes are multifactorial as genetic, metabolic and concomitant factors may influence the occurrence of drug hypersensitivity. Formation of drug protein adducts is considered a key step in drug adverse reactions, and in particular in the immunological recognition in drug hypersensitivity reactions. Nevertheless, non-covalent interactions of drugs with receptors in immune cells or with MHC clefts and/or exposed peptides can also play an important role. In recent years, development of proteomic approaches has allowed the identification and characterization of the protein targets for modification by drugs in vivo and in vitro, the nature of peptides exposed on MHC molecules, the changes in protein levels induced by drug treatment, and the concomitant modifications induced by danger signals, thus providing insight into context factors. Nevertheless, given the complexity and multifactorial nature of drug hypersensitivity reactions, understanding the underlying mechanisms also requires the integration of knowledge from genomic, metabolomic and clinical studies.

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Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA₁ and Clinically Used Prostaglandins

Cited by 17 publications

References 57 publications

PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

Asthma and allergic rhinitis associate with the rs2229542 variant that induces a p.Lys90Glu mutation and compromises AKR1B1 protein levels

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

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Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

Cited by 17 publications

References 57 publications

PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

Asthma and allergic rhinitis associate with the rs2229542 variant that induces a p.Lys90Glu mutation and compromises AKR1B1 protein levels

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

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Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA₁ and Clinically Used Prostaglandins