Lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer

Patrik Kovács, Tamás Csonka, Tünde Kovács, Zsanett Sári, Gyula Ujlaki, Adrien Sipos, Z. Karányi, Dóra Szeőcs, Csaba Hegedűs, Karen Uray, Laura Jankó, Máté Kiss, Borbála Kiss, Damya Laoui, L. Virág, G. Méhes, P. Bai, Edit Mikó

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number1255
JournalCancers
Volume11
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

Fingerprint

Lithocholic Acid
Microbiota
Oxidative Stress
Breast Neoplasms
Cytostatic Agents
Nitric Oxide Synthase Type II
Antioxidants
Proteins
Mitotic Index
Enzymes
Glutathione Peroxidase
G-Protein-Coupled Receptors
Sulfhydryl Compounds
Lipid Peroxidation
Down-Regulation
Pharmacology
Lipids
Survival

Keywords

  • 4HNE
  • Breast cancer
  • iNOS
  • Lithocholic acid
  • NRF2
  • Oxidative stress
  • Peroxynitrite

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kovács, P., Csonka, T., Kovács, T., Sári, Z., Ujlaki, G., Sipos, A., ... Mikó, E. (2019). Lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer. Cancers, 11(9), [1255]. https://doi.org/10.3390/cancers11091255

Lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer. / Kovács, Patrik; Csonka, Tamás; Kovács, Tünde; Sári, Zsanett; Ujlaki, Gyula; Sipos, Adrien; Karányi, Z.; Szeőcs, Dóra; Hegedűs, Csaba; Uray, Karen; Jankó, Laura; Kiss, Máté; Kiss, Borbála; Laoui, Damya; Virág, L.; Méhes, G.; Bai, P.; Mikó, Edit.

In: Cancers, Vol. 11, No. 9, 1255, 01.09.2019.

Research output: Contribution to journalArticle

Kovács, P, Csonka, T, Kovács, T, Sári, Z, Ujlaki, G, Sipos, A, Karányi, Z, Szeőcs, D, Hegedűs, C, Uray, K, Jankó, L, Kiss, M, Kiss, B, Laoui, D, Virág, L, Méhes, G, Bai, P & Mikó, E 2019, 'Lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer', Cancers, vol. 11, no. 9, 1255. https://doi.org/10.3390/cancers11091255
Kovács P, Csonka T, Kovács T, Sári Z, Ujlaki G, Sipos A et al. Lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer. Cancers. 2019 Sep 1;11(9). 1255. https://doi.org/10.3390/cancers11091255
Kovács, Patrik ; Csonka, Tamás ; Kovács, Tünde ; Sári, Zsanett ; Ujlaki, Gyula ; Sipos, Adrien ; Karányi, Z. ; Szeőcs, Dóra ; Hegedűs, Csaba ; Uray, Karen ; Jankó, Laura ; Kiss, Máté ; Kiss, Borbála ; Laoui, Damya ; Virág, L. ; Méhes, G. ; Bai, P. ; Mikó, Edit. / Lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer. In: Cancers. 2019 ; Vol. 11, No. 9.
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