Anticarcinogenic effects of ursodeoxycholic acid in pancreatic adenocarcinoma cell models

Patrik Kovács; Szandra Schwarcz; Petra Nyerges; Tímea Ingrid Bíró; Gyula Ujlaki; Péter Bai; Edit Mikó

doi:10.3389/fcell.2024.1487685

Anticarcinogenic effects of ursodeoxycholic acid in pancreatic adenocarcinoma cell models

Front Cell Dev Biol. 2024 Dec 11:12:1487685. doi: 10.3389/fcell.2024.1487685. eCollection 2024.

Authors

Patrik Kovács^#¹, Szandra Schwarcz^#¹, Petra Nyerges¹, Tímea Ingrid Bíró¹, Gyula Ujlaki¹, Péter Bai^{1

2

3

4}, Edit Mikó^{1

2}

Affiliations

¹ Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
² MTA-DE Lendület Laboratory of Cellular Metabolism, University of Debrecen, Debrecen, Hungary.
³ HUN-REN-UD Cell Biology and Signaling Research Group, Debrecen, Hungary.
⁴ Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

^# Contributed equally.

Abstract

Changes to the composition of the microbiome in neoplasia, is termed oncobiosis, may affect tumor behavior through the changes to the secretion of bacterial metabolites. In this study we show, that ursodeoxycholic acid (UDCA), a bacterial metabolite, has cytostatic properties in pancreatic adenocarcinoma cell (PDAC) models. UDCA in concentrations corresponding to the human serum reference range suppressed PDAC cell proliferation. UDCA inhibited the expression of epithelial mesenchymal transition (EMT)-related markers and invasion capacity of PDAC cells. UDCA treatment increased oxidative/nitrosative stress by reducing the expression of nuclear factor, erythroid 2-like 2 (NRF2), inducing inducible nitric oxide synthase (iNOS) and nitrotyrosine levels and enhancing lipid peroxidation. Furthermore, UDCA reduced the expression of cancer stem cell markers and the proportion of cancer stem cells. Suppression of oxidative stress by antioxidants, blunted the UDCA-induced reduction in cancer stemness. Finally, we showed that UDCA induced mitochondrial oxidative metabolism. UDCA did not modulate the effectiveness of chemotherapy agents used in the chemotherapy treatment of pancreatic adenocarcinoma. The antineoplastic effects of UDCA, observed here, may contribute to the induction of cytostasis in PDAC cell models by providing a more oxidative/nitrosative environment.

Keywords: bile acid; cancer stem cell; epithelial mesenchymal transition; oxidative phosphorylation; oxidative stress; ursodeoxycholic acid.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Our work was supported by the National Research, Development and Innovation Office of Hungary (grants K142141 and FK128387), the University of Debrecen, the Thematic Excellence Programme (TKP2021-EGA-19 and TKP2021-EGA-20) of the Ministry for Innovation and Technology in Hungary and the Hungarian Academy of Sciences (POST-COVID2021-33). The work was also supported by the ÚNKP-23 New National Excellence Program of the Ministry for Culture and Innovation from the Source of National Research, Development, and Innovation Fund (ÚNKP-23-4-I-DE-163, ÚNKP-23-3-II-DE-161, ÚNKP-23-3-II-DE-151, ÚNKP-23-3-I-DE-184). The work was supported by EKÖP fellowship (EKÖP-24-3-I-DE-147, EKÖP-24-4-I-DE-333, EKÖP-24-I-DE-386) of the University of Debrecen. This project has received funding from the HUN-REN Hungarian Research Network. Supported by the University of Debrecen Program for Scientific Publication.