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Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast c...

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Autores principales: Kovács, Patrik, Csonka, Tamás, Kovács, Tünde, Sári, Zsanett, Ujlaki, Gyula, Sipos, Adrien, Karányi, Zsolt, Szeőcs, Dóra, Hegedűs, Csaba, Uray, Karen, Jankó, Laura, Kiss, Máté, Kiss, Borbála, Laoui, Damya, Virág, László, Méhes, Gábor, Bai, Péter, Mikó, Edit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769524/
https://www.ncbi.nlm.nih.gov/pubmed/31461945
http://dx.doi.org/10.3390/cancers11091255
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author Kovács, Patrik
Csonka, Tamás
Kovács, Tünde
Sári, Zsanett
Ujlaki, Gyula
Sipos, Adrien
Karányi, Zsolt
Szeőcs, Dóra
Hegedűs, Csaba
Uray, Karen
Jankó, Laura
Kiss, Máté
Kiss, Borbála
Laoui, Damya
Virág, László
Méhes, Gábor
Bai, Péter
Mikó, Edit
author_facet Kovács, Patrik
Csonka, Tamás
Kovács, Tünde
Sári, Zsanett
Ujlaki, Gyula
Sipos, Adrien
Karányi, Zsolt
Szeőcs, Dóra
Hegedűs, Csaba
Uray, Karen
Jankó, Laura
Kiss, Máté
Kiss, Borbála
Laoui, Damya
Virág, László
Méhes, Gábor
Bai, Péter
Mikó, Edit
author_sort Kovács, Patrik
collection PubMed
description In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA–oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.
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spelling pubmed-67695242019-10-30 Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer Kovács, Patrik Csonka, Tamás Kovács, Tünde Sári, Zsanett Ujlaki, Gyula Sipos, Adrien Karányi, Zsolt Szeőcs, Dóra Hegedűs, Csaba Uray, Karen Jankó, Laura Kiss, Máté Kiss, Borbála Laoui, Damya Virág, László Méhes, Gábor Bai, Péter Mikó, Edit Cancers (Basel) Article In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA–oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis. MDPI 2019-08-27 /pmc/articles/PMC6769524/ /pubmed/31461945 http://dx.doi.org/10.3390/cancers11091255 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kovács, Patrik
Csonka, Tamás
Kovács, Tünde
Sári, Zsanett
Ujlaki, Gyula
Sipos, Adrien
Karányi, Zsolt
Szeőcs, Dóra
Hegedűs, Csaba
Uray, Karen
Jankó, Laura
Kiss, Máté
Kiss, Borbála
Laoui, Damya
Virág, László
Méhes, Gábor
Bai, Péter
Mikó, Edit
Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer
title Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer
title_full Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer
title_fullStr Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer
title_full_unstemmed Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer
title_short Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer
title_sort lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769524/
https://www.ncbi.nlm.nih.gov/pubmed/31461945
http://dx.doi.org/10.3390/cancers11091255
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