Next Article in Journal
Vitamin D Effects on Cell Differentiation and Stemness in Cancer
Previous Article in Journal
A Distinctive microRNA (miRNA) Signature in the Blood of Colorectal Cancer (CRC) Patients at Surgery
Article

Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress

1
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
2
MTA-DE Lendület Laboratory of Cellular Metabolism, 4032 Debrecen, Hungary
3
Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
4
Kenézy Breast Center at Kenézy Gyula County Hospital, 4032 Debrecen, Hungary
5
Department of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
6
Department of Surgery, Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, 3526 Miskolc, Hungary
7
Department of Pathology at Kenézy Gyula County Hospital, 4032 Debrecen, Hungary
8
Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
9
National Cancer Institute, National Institutes of Health, Bethesda, MD 20982, USA
10
Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2411; https://doi.org/10.3390/cancers12092411
Received: 12 August 2020 / Accepted: 20 August 2020 / Published: 25 August 2020
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. View Full-Text
Keywords: breast cancer; microbiome; oncobiome; indolepropionic acid; AHR; PXR; metastasis; oxidative stress; nitrosative stress; epithelial-to-mesenchymal transition breast cancer; microbiome; oncobiome; indolepropionic acid; AHR; PXR; metastasis; oxidative stress; nitrosative stress; epithelial-to-mesenchymal transition
Show Figures

Figure 1

MDPI and ACS Style

Sári, Z.; Mikó, E.; Kovács, T.; Jankó, L.; Csonka, T.; Lente, G.; Sebő, É.; Tóth, J.; Tóth, D.; Árkosy, P.; Boratkó, A.; Ujlaki, G.; Török, M.; Kovács, I.; Szabó, J.; Kiss, B.; Méhes, G.; Goedert, J.J.; Bai, P. Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress. Cancers 2020, 12, 2411. https://doi.org/10.3390/cancers12092411

AMA Style

Sári Z, Mikó E, Kovács T, Jankó L, Csonka T, Lente G, Sebő É, Tóth J, Tóth D, Árkosy P, Boratkó A, Ujlaki G, Török M, Kovács I, Szabó J, Kiss B, Méhes G, Goedert JJ, Bai P. Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress. Cancers. 2020; 12(9):2411. https://doi.org/10.3390/cancers12092411

Chicago/Turabian Style

Sári, Zsanett, 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, and Péter Bai. 2020. "Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress" Cancers 12, no. 9: 2411. https://doi.org/10.3390/cancers12092411

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop