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Ursodeoxycholic acid shows antineoplastic effects in bile duct cancer cells via apoptosis induction; p53 activation; and EGFR-ERK, COX-2, and PI3K-AKT pathway inhibition

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Abstract

Unlike in normal cells, ursodeoxycholic acid (UDCA) causes apoptosis rather than protection in cancer cells. Aim of this study was to demonstrate whether UDCA actually inhibits proliferation and induces apoptosis in bile duct cancer cells; the effect of UDCA on the expression of COX-2, PI3K/AKT, ERK, and EGFR; how UDCA affects cancer cell invasiveness and metastasis, since these effects are not established in bile duct cancer cells. SNU-245 cells (human extrahepatic bile duct cancer cells) were cultured. MTT assays were performed to evaluate the effect of UDCA on the cell proliferation. A cell death detection enzyme-linked immunosorbent assay and a caspase-3 activity assay were used to determine apoptosis. Western blot analysis measured expression levels of various proteins. The invasiveness of the cancer cells was evaluated by invasion assay. In cultured bile duct cancer cells, UDCA suppressed cell proliferation in bile duct cancer cells by inducing apoptosis and p53 activation, blocking deoxycholic acid (DCA)-induced activated EGFR-ERK signaling and COX-2, inhibiting DCA-induced activated PI3K-AKT signaling, and suppressing the invasiveness of bile duct cancer cells. In addition, a MEK inhibitor impaired UDCA-induced apoptosis in bile duct cancer cells. UDCA has antineoplastic and apoptotic effects in bile duct cancer cells. Thus, UDCA could be a chemopreventive agent in patients with a high risk of cancer, and/or a therapeutic option that enhances other chemotherapeutics.

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Abbreviations

UDCA:

Ursodeoxycholic acid

COX-2:

Cyclooxygenase-2

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

AKT:

Protein kinase B

ERK:

Extracellular signal-regulated kinase

MAPK:

Mitogen-activated protein kinase

MEK:

MAPK/ERK Kinase

DCA:

Deoxycholic acid

JNK:

C-Jun N-terminal kinase

BCL-2:

B-cell lymphoma 2

BAX:

BCL-2-like protein

CCA:

Cholangiocarcinoma

IGF-1R:

Insulin-like growth factor 1 receptor

mTOR:

Mammalian target of rapamycin

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Acknowledgements

This study was supported by Hallym Medical Center Academic-Industrial Cooperation Program (2016-323-I).

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Gangwon-Do, South Korea

    Jin Lee, Jung Han Kim, Jung Hee Kim, Jang Han Jung, Se Woo Park, Dong Hee Koh & Hyun Joo Jang

  2. Division of Gastroenterology, Hallym University Dongtan Sacred Heart Hospital, 7 Keunjaebong-Gil, Hwasung, Gyeonggi-Do, 18450, South Korea

    Jin Lee, Eun Mi Hong, Jung Hee Kim, Jang Han Jung, Se Woo Park, Dong Hee Koh & Hyun Joo Jang

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Contributions

JL performed the study design, data analysis, statistical analysis, data interpretation and manuscript drafting. EH performed conduction of main experiments. JK, JK, and JJ performed the data interpretation and critical revision: SP, DK, and HJ contributed to the study design and statistical analysis. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Jin Lee.

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All authors confirm that all data underlying the findings are fully available without restriction and have no conflict of interest to declare.

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Not applicable to the approval because this study was performed using cells purchased from the Korean Cell Line Bank (KCLB).

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Lee, J., Hong, E.M., Kim, J.H. et al. Ursodeoxycholic acid shows antineoplastic effects in bile duct cancer cells via apoptosis induction; p53 activation; and EGFR-ERK, COX-2, and PI3K-AKT pathway inhibition. Mol Biol Rep 48, 6231–6240 (2021). https://doi.org/10.1007/s11033-021-06331-y

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