Ursodeoxycholic acid inhibits epithelial‑mesenchymal transition, suppressing invasiveness of bile duct cancer cells: An in vitro study

Abstract

Epithelial-mesenchymal transition (EMT) features are associated with pathological severity in the progression and metastasis of various cancer types, including bile duct cancer (BDC). Our previous study demonstrated that ursodeoxycholic acid (UDCA) blocked the EGFR-MAPK signaling pathway and inhibited the invasion of BDC cells. The present study was performed to determine whether UDCA inhibits EMT and promotes the expression of E-cadherin to inhibit the invasion and aggressiveness of BDC. In addition, the present study aimed to confirm that the primary mechanism of inhibition of EMT by UDCA is related to the EGFR axis. Human extrahepatic BDC cells were cultured. The effect of UDCA on cell proliferation was evaluated using MTT assays. A cell death ELISA kit was used to measure apoptosis, and western blot assays or immunofluorescence staining assays measured the expression levels of various target proteins. The mRNA expression of Slug and ZEB1 was evaluated via reverse transcription-quantitative PCR. The invasiveness of BDC cells was estimated by invasion assays and western blot assays for focal adhesion kinase (FAK). UDCA inhibited the proliferation of BDC cells as effectively as gefitinib (an EGFR inhibitor), and the combination of UDCA and gefitinib revealed an additive effect on the proliferation of cells. UDCA and gefitinib induced apoptosis, and the combination of UDCA and gefitinib demonstrated an additive effect on apoptosis in BDC cells. UDCA restored the E-cadherin expression inhibited by EGF and suppressed N-cadherin expression increased by EGF as effectively as gefitinib. UDCA suppressed the Slug and ZEB1 mRNA expression induced by EGF in BDC cells. UDCA suppressed the invasiveness of BDC cells and FAK expression linked to the invasiveness of BDC. In conclusion, UDCA enhanced E-cadherin expression and suppressed N-cadherin expression through inhibition of the EGF-EGFR axis, contributing to the inhibition of EMT and invasiveness in BDC cells. Therefore, UDCA may be applied as an adjuvant or palliative antineoplastic agent and as a therapeutic option to enhance the effect of other chemotherapeutics.

The anticancer activity of bile acids in drug discovery and development

“…UDCA inhibited the growth of cholangiocarcinoma, and the combined UDCA and gefitinib displayed a more robust effect. Thus, UDCA demonstrates a potential adjuvant or palliative anticancer drug, providing a therapeutic option to enhance the effects of other chemotherapeutic agents synergistically ( Lee et al, 2022 ). UDCA suppressed cholangiocarcinoma cell proliferation and invasiveness by triggering apoptosis, activating p53, and blocking DCA-induced activated EGFR-ERK and PI3K-AKT signaling ( Lee et al, 2021 ).…”

“…Furthermore, various factors, including gene mutations for the BA synthesis and transport, high-fat diets, medications, and circadian rhythm disturbances, are found to mediate the pathologies of multiple diseases that involve cholestatic liver disease, inflammatory bowel disease, diabetes, obesity, tumors, and related metabolic disorders ( Li and Chiang, 2014 ; Fiorucci et al, 2021 ; Fu et al, 2021 ; Perino et al, 2021 ; Yang et al, 2021 ; Shi et al, 2023 ). In recent years, several researches have demonstrated that BAs have antitumor properties in various cancer cell types, such as tamoxifen-resistant breast cancer ( Luu et al, 2018 ; Kovács et al, 2019 ), oral squamous cell carcinoma ( Talebian et al, 2020 ), cholangiocarcinoma ( Lee et al, 2022 ), gastric cancer ( Zhang et al, 2022 ), colon cancer ( Kim E. K. et al, 2017 ), hepatocellular carcinoma ( Fan et al, 2023 ), prostate cancer ( Lee et al, 2017 ), gallbladder cancer ( Lin et al, 2020 ; Li et al, 2022 ), neuroblastoma ( Trah et al, 2020 ) etc., by inhibiting cancer cell proliferation and migration. In addition, new BA derivatives have been synthesized in several laboratories to investigate their anticancer properties.…”

Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy

“…The combination of UDCA, an FXR antagonist with the targeted therapeutic drug sorafenib, shows an efficacious response in HCC by inhibiting cell proliferation and inducing apoptosis through the reactive-oxygen-species-dependent activation of ERK and the dephosphorylation of STAT3 [ 211 ]. Similarly, an in vitro study demonstrates that UDCA, in combination with gefitinib, an EGFR-tyrosine kinase inhibitor, inhibits EMT and suppresses the invasiveness of BTC cells [ 212 ]. The combination of FXR agonists/antagonist with anti-cancer drugs is summarized in Table 2 .…”

Ursodeoxycholic Acid Suppresses Epithelial-Mesenchymal Transition via Inhibition of Reactive Oxygen Species in Bile Duct Cancer Cells

“…억제함으로써 항종양 효과의 증거를 제시한 바 있다. 17 활성산소(reactive oxygen species, ROS)는 산소의 환원에 의해 발생하는데, 악성 세포의 세포주기 진행, 증식, 생존, 세포자멸사, 그리고 혈관생성에 영향을 준다. 18 Raf, Myc, 그리고 cyclin E와 같은 발암유전자의 과발현은 ROS 생성의 증가와 연관이 있으며, 19 또한 일부 연구에서 ROS는 EMT 과정의 중개자(mediator) 또는 조율자(modulator)로 여겨지고 있다.…”