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Cancers (Basel). 2019 Aug 27;11(9). pii: E1255. doi: 10.3390/cancers11091255.

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

Author information

1
Departments of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
2
Departments of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
3
Departments of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
4
Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
5
Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium.
6
Departments of Dermatology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
7
Departments of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. baip@med.unideb.hu.
8
MTA-DE Lendület Laboratory of Cellular Metabolism, 4032 Debrecen, Hungary. baip@med.unideb.hu.
9
Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. baip@med.unideb.hu.
10
Departments of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary. miko.edit@med.unideb.hu.
11
MTA-DE Lendület Laboratory of Cellular Metabolism, 4032 Debrecen, Hungary. miko.edit@med.unideb.hu.

Abstract

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.

KEYWORDS:

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

PMID:
31461945
DOI:
10.3390/cancers11091255
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