PMID- 32854297 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201027 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 12 IP - 9 DP - 2020 Aug 25 TI - Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress. LID - 10.3390/cancers12092411 [doi] LID - 2411 AB - 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. FAU - Sari, Zsanett AU - Sari Z AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Miko, Edit AU - Miko E AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. AD - MTA-DE Lendulet Laboratory of Cellular Metabolism, 4032 Debrecen, Hungary. FAU - Kovacs, Tunde AU - Kovacs T AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Janko, Laura AU - Janko L AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Csonka, Tamas AU - Csonka T AD - Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Lente, Greta AU - Lente G AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Sebo, Eva AU - Sebo E AD - Kenezy Breast Center at Kenezy Gyula County Hospital, 4032 Debrecen, Hungary. FAU - Toth, Judit AU - Toth J AD - Department of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Toth, Dezso AU - Toth D AD - Department of Surgery, Borsod-Abauj-Zemplen County Hospital and University Teaching Hospital, 3526 Miskolc, Hungary. FAU - Arkosy, Peter AU - Arkosy P AD - Department of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Boratko, Anita AU - Boratko A AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Ujlaki, Gyula AU - Ujlaki G AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Torok, Miklos AU - Torok M AD - Department of Pathology at Kenezy Gyula County Hospital, 4032 Debrecen, Hungary. FAU - Kovacs, Ilona AU - Kovacs I AD - Department of Pathology at Kenezy Gyula County Hospital, 4032 Debrecen, Hungary. FAU - Szabo, Judit AU - Szabo J AUID- ORCID: 0000-0002-9216-8649 AD - Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Kiss, Borbala AU - Kiss B AD - Department of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Mehes, Gabor AU - Mehes G AD - Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. FAU - Goedert, James J AU - Goedert JJ AD - National Cancer Institute, National Institutes of Health, Bethesda, MD 20982, USA. FAU - Bai, Peter AU - Bai P AUID- ORCID: 0000-0002-6191-6616 AD - Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. AD - MTA-DE Lendulet Laboratory of Cellular Metabolism, 4032 Debrecen, Hungary. AD - Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. LA - eng GR - K123975/Hungarian Scientific Research Fund/ GR - FK128387/Hungarian Scientific Research Fund/ GR - PD124110/Hungarian Scientific Research Fund/ GR - GINOP-2.3.2-15-2016-00006/Hungarian Scientific Research Fund/ GR - Momentum fellowship/Magyar Tudomanyos Akademia/ GR - Bolyai Fellowship/Magyar Tudomanyos Akademia/ GR - Z01CP010214/CA/NCI NIH HHS/United States GR - NKFIH-1150-6/2019/Hungarian Scientific Research Fund/ GR - UNKP-19-4-DE-79/Hungarian Scientific Research Fund/ PT - Journal Article DEP - 20200825 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC7565149 OTO - NOTNLM OT - AHR OT - PXR OT - breast cancer OT - epithelial-to-mesenchymal transition OT - indolepropionic acid OT - metastasis OT - microbiome OT - nitrosative stress OT - oncobiome OT - oxidative stress COIS- The authors have no competing financial or non-financial interests to declare. EDAT- 2020/08/29 06:00 MHDA- 2020/08/29 06:01 PMCR- 2020/08/25 CRDT- 2020/08/29 06:00 PHST- 2020/08/12 00:00 [received] PHST- 2020/08/20 00:00 [accepted] PHST- 2020/08/29 06:00 [entrez] PHST- 2020/08/29 06:00 [pubmed] PHST- 2020/08/29 06:01 [medline] PHST- 2020/08/25 00:00 [pmc-release] AID - cancers12092411 [pii] AID - cancers-12-02411 [pii] AID - 10.3390/cancers12092411 [doi] PST - epublish SO - Cancers (Basel). 2020 Aug 25;12(9):2411. doi: 10.3390/cancers12092411.