Inhibition of protein kinase C activity by the antirheumatic drug auranofin

Froscio, Mario; Murray, Andrew W.; Hurst, N P

doi:10.1016/0006-2952(89)90061-0

Cited by 27 publications

(8 citation statements)

References 9 publications

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“…We tested the later possibility by using auranofin, a potent inhibitor of TR (IC 50 ϭ 20 nM). Auranofin inhibits other selenoenzymes such as glutathione peroxidase, and other sulfhydryl enzymes such as glutathione reductase and PKC only at micromolar concentrations (54,55). Because the TR system can reverse the MSA-induced redox modification of PKC in purified form (Fig.…”

Section: Possible Role Of the Tr System In Reversing Msa-induced Pkc mentioning

confidence: 99%

Locally Generated Methylseleninic Acid Induces Specific Inactivation of Protein Kinase C Isoenzymes

Gundimeda

Schiffman

Chhabra

et al. 2008

Journal of Biological Chemistry

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In this study, we show that methylselenol, a selenometabolite implicated in cancer prevention, did not directly inactivate protein kinase C (PKC). Nonetheless, its oxidation product, methylseleninic acid (MSA), inactivated PKC at low micromolar concentrations through a redox modification of vicinal cysteine sulfhydryls in the catalytic domain of PKC. This modification of PKC that occurred in both isolated form and in intact cells was reversed by a reductase system involving thioredoxin reductase, a selenoprotein. PKC isoenzymes exhibited variable sensitivity to MSA with Ca 2؉ -dependent PKC isoenzymes (␣, ␤, and ␥) being the most susceptible, followed by isoenzymes ␦ and ⑀. Other enzymes tested were inactivated only with severalfold higher concentrations of MSA than those required for PKC inactivation. This specificity for PKC was further enhanced when MSA was generated within close proximity to PKC through a reaction of methylselenol with PKC-bound lipid peroxides in the membrane. The MSA-methylselenol redox cycle resulted in the catalytic oxidation of sulfhydryls even with nanomolar concentrations of selenium. MSA inhibited cell growth and induced apoptosis in DU145 prostate cancer cells at a concentration that was higher than that needed to inhibit purified PKC␣ but in a range comparable with that required for the inhibition of PKC⑀. This MSA-induced growth inhibition and apoptosis decreased with a conditional overexpression of PKC⑀ and increased with its knock-out by small interfering RNA. Conceivably, when MSA is generated within the vicinity of PKC, it specifically inactivates PKC isoenzymes, particularly the promitogenic and prosurvival ⑀ isoenzyme, and this inactivation causes growth inhibition and apoptosis.

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Section: Possible Role Of the Tr System In Reversing Msa-induced Pkc mentioning

confidence: 99%

Locally Generated Methylseleninic Acid Induces Specific Inactivation of Protein Kinase C Isoenzymes

Gundimeda

Schiffman

Chhabra

et al. 2008

Journal of Biological Chemistry

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“…Genes that encode protein-modifying enzymes such as protein kinase domain-containing proteins (EHI_186820) (EHI_101280) and Protein kinase (EHI_188110), which are also oxidized in acute AF trophozoites [ 28 ]: Protein kinases have been associated with the virulence and phagocytic activity of E. histolytica [ 53 ]. The redox regulation of protein kinases is well established [ 54 ], and it has been demonstrated that AF can directly inhibit protein kinase C by interacting with thiol groups present in the catalytic site [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Entamoeba histolytica Adaption to Auranofin: A Phenotypic and Multi-Omics Characterization

et al. 2021

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Auranofin (AF), an antirheumatic agent, targets mammalian thioredoxin reductase (TrxR), an important enzyme controlling redox homeostasis. AF is also highly effective against a diversity of pathogenic bacteria and protozoan parasites. Here, we report on the resistance of the parasite Entamoeba histolytica to 2 µM of AF that was acquired by gradual exposure of the parasite to an increasing amount of the drug. AF-adapted E. histolytica trophozoites (AFAT) have impaired growth and cytopathic activity, and are more sensitive to oxidative stress (OS), nitrosative stress (NS), and metronidazole (MNZ) than wild type (WT) trophozoites. Integrated transcriptomics and redoxomics analyses showed that many upregulated genes in AFAT, including genes encoding for dehydrogenase and cytoskeletal proteins, have their product oxidized in wild type trophozoites exposed to AF (acute AF trophozoites) but not in AFAT. We also showed that the level of reactive oxygen species (ROS) and oxidized proteins (OXs) in AFAT is lower than that in acute AF trophozoites. Overexpression of E. histolytica TrxR (EhTrxR) did not protect the parasite against AF, which suggests that EhTrxR is not central to the mechanism of adaptation to AF.

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“…Protein kinases have been associated with virulence and phagocytic activity of E.histolytica [54]. The redox regulation of protein kinases is well established [55] and it has been demonstrated that AF can directly inhibit protein kinase C by interacting with thiol groups present in the catalytic site [56].…”

Section: Discussionmentioning

confidence: 99%

Entamoeba histolytica adaption to auranofin: a phenotypic and multi-omics characterization

Shaulov

Sarid

Trebicz-Geffen

et al. 2021

Preprint

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Auranofin (AF), an antirheumatic agent, targets mammalian thioredoxin reductase (TrxR), an important enzyme controlling redox homeostasisis, AF is also very effective against a diversity of pathogenic bacteria and protozoan parasites. Here, we report about the resistance of the parasite Entamoeba histolytica to 2 microM of AF that has been acquired by gradual exposure of the parasite to increasing amount of the drug. AF adapted E.histolytica trophozoites (AFAT) has an impaired growth, cytopathic activity and they are more sensitive to oxidative stress (OS), nitrosative stress (NS) and metronidazole (MTZ) than wild type (WT) trophozoites. Integrated transcriptomics and redoxomics analyses showed that many upregulated genes in AFAT, including genes encoding for dehydrogenase and cytoskeletal proteins, have their product oxidized in wild type trophozoites exposed to AF (acute AF trophozoites) but not in AFAT. We also showed that the level of reactive oxygen species (ROS) and oxidized proteins (OXs) in AFAT is lower than that of acute AF trophozoites. Overexpression of E.histolytica TrxR (EhTrxR) did not protect the parasite against AF which suggests that EhTrxR is not central is the mechanism of adaptation to AF.

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Inhibition of protein kinase C activity by the antirheumatic drug auranofin

Cited by 27 publications

References 9 publications

Locally Generated Methylseleninic Acid Induces Specific Inactivation of Protein Kinase C Isoenzymes

Locally Generated Methylseleninic Acid Induces Specific Inactivation of Protein Kinase C Isoenzymes

Entamoeba histolytica Adaption to Auranofin: A Phenotypic and Multi-Omics Characterization

Entamoeba histolytica adaption to auranofin: a phenotypic and multi-omics characterization

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