Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress
Oncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indol...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/9/2411 |
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| author | Zsanett Sári Edit Mikó Tünde Kovács Laura Jankó Tamás Csonka Gréta Lente Éva Sebő Judit Tóth Dezső Tóth Péter Árkosy Anita Boratkó Gyula Ujlaki Miklós Török Ilona Kovács Judit Szabó Borbála Kiss Gábor Méhes James J. Goedert Péter Bai |
| author_facet | Zsanett Sári Edit Mikó Tünde Kovács Laura Jankó Tamás Csonka Gréta Lente Éva Sebő Judit Tóth Dezső Tóth Péter Árkosy Anita Boratkó Gyula Ujlaki Miklós Török Ilona Kovács Judit Szabó Borbála Kiss Gábor Méhes James J. Goedert Péter Bai |
| author_sort | Zsanett Sári |
| collection | DOAJ |
| description | Oncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indolepropionic acid (IPA), a bacterial tryptophan metabolite, has cytostatic properties. IPA selectively targeted breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and metastasis formation of cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in cancer cell stem-ness. IPA exerted its effects through aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in breast cancer. Furthermore, AHR activation and PXR expression related inversely to cancer cell proliferation level and to the stage and grade of the tumor. The fecal microbiome’s capacity for IPA biosynthesis was suppressed in women newly diagnosed with breast cancer, especially with stage 0. Bacterial indole biosynthesis showed correlation with lymphocyte infiltration to tumors in humans. Taken together, we found that IPA is a cytostatic bacterial metabolite, the production of which is suppressed in human breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease. |
| first_indexed | 2024-03-10T16:51:44Z |
| format | Article |
| id | doaj.art-5a077690a4674d89b71f6ab3cb23ab69 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T16:51:44Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5a077690a4674d89b71f6ab3cb23ab692023-11-20T11:17:07ZengMDPI AGCancers2072-66942020-08-01129241110.3390/cancers12092411Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative StressZsanett Sári0Edit Mikó1Tünde Kovács2Laura Jankó3Tamás Csonka4Gréta Lente5Éva Sebő6Judit Tóth7Dezső Tóth8Péter Árkosy9Anita Boratkó10Gyula Ujlaki11Miklós Török12Ilona Kovács13Judit Szabó14Borbála Kiss15Gábor Méhes16James J. Goedert17Péter Bai18Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryKenézy Breast Center at Kenézy Gyula County Hospital, 4032 Debrecen, HungaryDepartment of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Surgery, Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, 3526 Miskolc, HungaryDepartment of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Pathology at Kenézy Gyula County Hospital, 4032 Debrecen, HungaryDepartment of Pathology at Kenézy Gyula County Hospital, 4032 Debrecen, HungaryDepartment of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryNational Cancer Institute, National Institutes of Health, Bethesda, MD 20982, USADepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryOncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indolepropionic acid (IPA), a bacterial tryptophan metabolite, has cytostatic properties. IPA selectively targeted breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and metastasis formation of cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in cancer cell stem-ness. IPA exerted its effects through aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in breast cancer. Furthermore, AHR activation and PXR expression related inversely to cancer cell proliferation level and to the stage and grade of the tumor. The fecal microbiome’s capacity for IPA biosynthesis was suppressed in women newly diagnosed with breast cancer, especially with stage 0. Bacterial indole biosynthesis showed correlation with lymphocyte infiltration to tumors in humans. Taken together, we found that IPA is a cytostatic bacterial metabolite, the production of which is suppressed in human breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease.https://www.mdpi.com/2072-6694/12/9/2411breast cancermicrobiomeoncobiomeindolepropionic acidAHRPXR |
| spellingShingle | Zsanett Sári Edit Mikó Tünde Kovács Laura Jankó Tamás Csonka Gréta Lente Éva Sebő Judit Tóth Dezső Tóth Péter Árkosy Anita Boratkó Gyula Ujlaki Miklós Török Ilona Kovács Judit Szabó Borbála Kiss Gábor Méhes James J. Goedert Péter Bai Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress Cancers breast cancer microbiome oncobiome indolepropionic acid AHR PXR |
| title | Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress |
| title_full | Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress |
| title_fullStr | Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress |
| title_full_unstemmed | Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress |
| title_short | Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress |
| title_sort | indolepropionic acid a metabolite of the microbiome has cytostatic properties in breast cancer by activating ahr and pxr receptors and inducing oxidative stress |
| topic | breast cancer microbiome oncobiome indolepropionic acid AHR PXR |
| url | https://www.mdpi.com/2072-6694/12/9/2411 |
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