Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer

Cancers

Borbála Kiss¹  Zsolt Karányi²  Karen Uray³  Péter Bai³  László Virág³  Laura Jankó³  Dóra Szeőcs³  Patrik Kovács³  Tünde Kovács³  Gyula Ujlaki³  Zsanett Sári³  Edit Mikó³  Adrien Sipos³  Csaba Hegedűs³  Tamás Csonka⁴  Gábor Méhes⁴  Máté Kiss⁵  Damya Laoui⁵ 

[1] Departments of Dermatology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;Departments of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;Departments of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;Departments of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium;

关键词: lithocholic acid;    oxidative stress;    breast cancer;    NRF2;    iNOS;    peroxynitrite;    4HNE;   

DOI  :  10.3390/cancers11091255

来源: DOAJ

【 摘 要 】

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA−oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.

【 授权许可】

Unknown