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

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Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress cancers Article Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress Zsanett Sári 1, Edit Mikó 1,2, Tünde Kovács 1, Laura Jankó 1, Tamás Csonka 3, Gréta Lente 1, Éva Seb˝o 4, Judit Tóth 5, Dezs˝oTóth 6,Péter Árkosy 5, Anita Boratkó 1, Gyula Ujlaki 1, Miklós Török 7, Ilona Kovács 7, Judit Szabó 8 , Borbála Kiss 5,Gábor Méhes 3, James J. Goedert 9 and Péter Bai 1,2,10,* 1 Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; [email protected] (Z.S.); [email protected] (E.M.); [email protected] (T.K.); [email protected] (L.J.); [email protected] (G.L.); [email protected] (A.B.); [email protected] (G.U.) 2 MTA-DE Lendület Laboratory of Cellular Metabolism, 4032 Debrecen, Hungary 3 Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; [email protected] (T.C.); [email protected] (G.M.) 4 Kenézy Breast Center at Kenézy Gyula County Hospital, 4032 Debrecen, Hungary; [email protected] 5 Department of Oncology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; [email protected] (J.T.); [email protected] (P.Á.); [email protected] (B.K.) 6 Department of Surgery, Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, 3526 Miskolc, Hungary; [email protected] 7 Department of Pathology at Kenézy Gyula County Hospital, 4032 Debrecen, Hungary; [email protected] (M.T.); [email protected] (I.K.) 8 Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; [email protected] 9 National Cancer Institute, National Institutes of Health, Bethesda, MD 20982, USA; [email protected] 10 Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary * Correspondence: [email protected]; Tel.: +36-52-412-345; Fax: +36-52-412-566 Received: 12 August 2020; Accepted: 20 August 2020; Published: 25 August 2020 Abstract: 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 Cancers 2020, 12, 2411; doi:10.3390/cancers12092411 www.mdpi.com/journal/cancers Cancers 2020, 12, 2411 2 of 27 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. Keywords: breast cancer; microbiome; oncobiome; indolepropionic acid; AHR; PXR; metastasis; oxidative stress; nitrosative stress; epithelial-to-mesenchymal transition 1. Introduction Dysbiotic microbiota, associated with oncological diseases, is termed the oncobiome. Oncobiosis of the distal gut is associated with breast cancer [1–11]; importantly, among the oncobiome studies, common microbiome changes were identified [12,13], suggesting a common root for the pathogenic role of the oncobiome. It remained a question of whether oncobiotic transformation of the microbiome has a causative role in carcinogenesis in breast cancer or if it is an epiphenomenon. Perturbing the microbiota by antibiotic treatment exacerbated breast cancer in an animal model [14], and there is suggestive supportive evidence in human population studies [15–22]. In good agreement with that, probiotic treatment may be protective against the incidence of breast cancer [23–26]. Taken together, the oncobiome could have a causative role in carcinogenesis. While there have been several studies of potential oncobiosis in breast cancer, much less is known about how oncobiosis affects breast cancer cells and the pathways by which it may contribute to carcinogenesis. The oncobiome changes the behavior of breast cancer cells at multiple points. Change from eubiosis to oncobiosis induces epithelial-to-mesenchymal transition (EMT) [27–29]; promotes migration and invasion [28]; reduces oxidative stress [30]; induces widespread metabolic alterations [27,28] in cancers cells; alters the differentiation of cancer stem cells [28]; and suppresses antitumor immunity [27,31]. These oncogenic processes support tumor growth [27,28], tumor infiltration to the surrounding tissues [27,28], and metastasis formation [27,28,31,32]. Moreover, the oncobiome has enhanced capacity to increase systemic estrogen levels by increasing enterohepatic circulation [1,2,5]. The parent estrogens, estrone and estradiol, increase cell proliferation, and their catechol–quinone metabolites cause oxidative DNA damage and mutagenesis [33]. The microbiome also can interfere with the chemoradiotherapy and immunotherapy of breast cancer [34–36]. The actual molecular mechanisms through which the microbiome and cancer cells interact are yet not characterized in detail. Nevertheless, there are two major routes identified to date. The physical presence of the bacteria and their physical interaction with immune cells fine-tune the immune system that directly impacts on the efficacy of immune therapies and antitumor immunity [20,35,37,38]. Additionally, bacterial metabolites can provide a link between the microbiome and cancer cells through the circulation [34]. Among these metabolites, short-chain fatty acids, lithocholic acid, and cadaverine have cytostatic properties [27,28,34,39]. In breast cancer, the metabolic capacity of the microbiome is suppressed [4,27], suggesting that the production of cytostatic metabolites decrease in breast cancer. Indolepropionic acid (IPA) is a bacterial metabolite that is produced by the deamination of tryptophan [28,40]. The enzyme responsible for the formation of indolepropionic acid is tryptophanase (TnaA) [40]. Approximately, 4–6% of tryptophan is metabolized to indole derivatives through bacterial enzymes [41]. In germ-free mice, serum tryptophan levels increase, highlighting the burden of microbial degradation on tryptophan levels [42–46]. It is of note that besides the indicated indole derivatives, the microbiome is capable of synthesizing a large set of other indole-derivative metabolites [46,47]. In the pathway that yields IPA, tryptophan is converted to indole lactate, then to indole acrylic acid, and subsequently to IPA [48]. In this study, we assessed the cytostatic properties of a bacterial metabolite, IPA, as well as changes to its production in women with breast cancer. Cancers 2020, 12, 2411 3 of 27 2. Materials and Methods All methods were performed according to the relevant guidelines. 2.1. Chemicals Chemicals, among them, indolepropionic acid (IPA), glutathione (GSH), N-acetyl-cysteine (NAC), Mito-TEMPO, and ketoconazole were from Sigma-Aldrich (St. Louis, MO, USA) unless otherwise stated. IPA was used, 0.4 µM and 0.8 µM, which corresponds to the normal human serum concentration of IPA [40,49,50]. GSH and NAC antioxidants were used at a final concentration of 5 mM. The mitochondria-targeted antioxidant Mito-TEMPO was used at a concentration of 5 µM. The aryl hydrocarbon receptor (AHR) inhibitor, CH223191, was obtained from MedChemExpress (MCE, Monmouth Junction, NJ, USA) and was applied at a concentration of 10 µM. Pregnane X receptor (PXR) downstream signaling was inhibited using ketoconazole at a final concentration of 25 µM[51,52]. The Silencer Select siRNAs targeting AHR (AHR—siRNA ID: s1198) and PXR (NR1I2—siRNA ID: s16910) and the negative control siRNA #1 (cat.no. 4390843) were obtained from Thermo Fisher Scientific (Waltham, MA, USA) and each was used at a final concentration of 30 nM. 2.2. Cell Culture 4T1murinebreastcancercellsweremaintainedinRPMI-1640(Sigma-Aldrich, R5886)mediumcontaining 10% FBS, 1% penicillin/streptomycin, 2 mM L-glutamine, and 1% pyruvate
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