Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

Abstract

Changes to bacterial metabolite-elicited signaling, in oncobiosis associated with breast cancer, plays a role in facilitating the progression of the disease. We show that indoxyl-sulfate (IS), a tryptophan metabolite, has cytostatic properties in models of breast cancer. IS supplementation, in concentrations corresponding to the human serum reference range, suppressed tumor infiltration to the surrounding tissues and metastasis formation in a murine model of breast cancer. In cellular models, IS suppressed NRF2 and induced iNOS, leading to induction of oxidative and nitrosative stress, and, consequently, reduction of cell proliferation; enhanced oxidative and nitrosative stress are crucial in the subsequent cytostasis. IS also suppressed epithelial-to-mesenchymal transition vital for suppressing cellular movement and diapedesis. Furthermore, IS rendered cells hypometabolic, leading to a reduction in aldehyde-dehydrogenase positive cells. Pharmacological inhibition of the pregnane-X receptor using CH223191 and the aryl-hydrocarbon receptor using ketoconazole diminished the IS-elicited effects, suggesting that these receptors were the major receptors of IS in these models. Finally, we showed that increased expression of the human enzymes that form IS (Cyp2E1, Sult1A1, and Sult1A2) is associated with better survival in breast cancer, an effect that is lost in triple negative cases. Taken together, IS, similar to indolepropionic acid (another tryptophan metabolite), has cytostatic properties and higher expression of the metabolic machinery responsible for the formation of IS supports survival in breast cancer.

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

“…To that end, we tried to revert the cytostatic effects of ruthenium complexes using strong reductants such as reduced glutathione (GSH) and N -acetyl-cysteine (NAC). Furthermore, we also tested MitoTEMPO, a mitochondrially targeted antioxidant that can efficiently detoxify mitochondria-derived reactive oxygen species [ 45 , 46 ]. GSH and NAC cotreatment attenuated the cytostatic effects induced by Ru-2a , Ru-4 , Ru-6 , and Ru-8 ( Figure 9 A) pointing to the causative role of reactive oxygen species production in cytostasis.…”

Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma

“…As AHR activity in tumor-associated macrophages and in T cells has previously been shown to promote tumor progression by diverse mechanisms including the upregulation of adenosine production 89 and immune checkpoint molecule expression 90 , these results suggest that Trp metabolism and AHR activation in glioblastoma may contribute to glioblastoma immune evasion. However, AHR activation does not always necessarily promote cancer as it also exerts tumor-suppressive effects and has been shown to inhibit tumor formation 91 - 93 and metastasis 94 - 96 . These divergent effects of the AHR in cancer likely stem from the complexity of its activation and effects, which are cell type-, ligand- and context-specific 43 , 97 .…”

The role of the microbiome in ovarian cancer: mechanistic insights into oncobiosis and to bacterial metabolite signaling

“…Microbiome-neoplastic cell interactions are multi-pronged (Miko et al 2016 ; Miko et al 2019 ; Zitvogel et al 2017 ; Kovacs et al 2020 ; Finlay et al 2020 ) and can impact on multiple cancer hallmarks (for cancer hallmarks, see the seminal papers of Hanahan and Weinberg (Hanahan and Weinberg 2011 , 2000 )). Microbiome-related effects stem from basic cellular functions, such as changes to redox homeostasis (Kovács et al 2019 ; Smolková et al 2020 ; Sári et al 2020a , b ) or changes to cellular metabolism (Sári et al 2020a , b ; Miko et al 2018 ; Kovács et al 2019 ), via altered gene expression patterns. These primary changes then modulate larger scale events, namely, epithelial-to-mesenchymal transition (Sári et al 2020b ; Miko et al 2018 ; Kovács et al 2019 ; Buchta Rosean et al 2019 ; Ingman 2019 ; Vergara et al 2019 ), cancer cellular movement, invasion, diapedesis and metastasis formation (Kovács et al 2019 ; Sári et al 2020a , b , 2020 ; Miko et al 2018 ; Kovács et al 2019 ), angiogenesis (Miko et al 2018 ), the modulation of antitumor immunity (Sári et al 2020a ; Miko et al 2018 ; Vergara et al 2019 ; Sipe et al 2020 ; Osman and Luke 2019 ; Zitvogel et al 2016 ; Routy et al 2018a , 2018b ; Gopalakrishnan et al 2018 ; Elkrief et al 2019 ; Derosa et al 2020 ; Hall and Versalovic 2018 ; Viaud et al 2014 ), and tumor-promoting inflammation (Kiss et al 2020 ; Yu 2018 ).…”

“…In this case, the dysbiotic microbiome drives local inflammation upon pathological colonization, such as in ovarian carcinoma (Wang et al 2020 ) or pancreas adenocarcinoma (Kiss et al 2020 ). On the contrary, low oxidative stress, induced by bacterial metabolites, can exert cytostatic (but not cytotoxic) properties, as in the downregulation of NRF2 in breast cancer (Kovács et al 2019 ; Sári et al 2020a , b ).…”