Journal Article

Inhibition of Wnt/β‐catenin signaling downregulates P‐glycoprotein and reverses multi‐drug resistance of cholangiocarcinoma

Shen, Dong‐Yan, Liu, Chang‐Qin, Zhang, Wei, Zeng, Xin

2013

Overview

The development of multi‐drug resistance (MDR) represents a major obstacle in the successful treatment of cancers. However, the factors and mechanisms that lead to MDR in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remain unclear. In this study, we established a human MDR CCA cell line QBC939/5‐FU. Compared with QBC939 cells, a rounder shape, a higher nuclear–cytoplasmic ratio, a shorter cell cycle, faster growth and resistance to chemotherapeutics are major characteristics of QBC939/5‐FU cells. P‐glycoprotein (P‐gp) and β‐catenin were upregulated in QBC939/5‐FU cells. Furthermore, the drug susceptibility of QBC939 cells to common chemotherapeutics was significantly decreased after Wnt3a treatment, whereas inhibition of Wnt/β‐catenin pathway by β‐catenin siRNA reversed the MDR of QBC939/5‐FU cells to chemotherapeutics. Molecular study revealed that activation of Wnt/β‐catenin pathway resulted in upregulation of P‐gp and contributed to MDR of QBC939/5‐FU cells. Extraction of Siamese Crocodile 3 (ESC‐3) bile enhanced the drug sensitivity of QBC939/5‐FU cells to 5‐FU, paralleled with downregulation of β‐catenin and P‐gp. The association of Wnt/β‐catenin pathway and P‐gp was further confirmed by the clinical data for CCA tissues. Our study represents the first implication of Wnt/β‐catenin activation in the MDR of CCA, which may be a beneficial target for the clinical treatment of CCA.

• Publisher: John Wiley and Sons Inc
• Subject: Alligators and Crocodiles / Animals / Antineoplastic Agents - pharmacology / ATP Binding Cassette Transporter, Subfamily B - biosynthesis / ATP Binding Cassette Transporter, Subfamily B - genetics / ATP-Binding Cassette Sub-Family B Member 4 / beta Catenin - antagonists & inhibitors / beta Catenin - genetics / Bile - chemistry / Bile Duct Neoplasms - genetics / Bile Duct Neoplasms - metabolism / Bile Ducts, Intrahepatic - metabolism / Cell Cycle / Cell Line, Tumor - drug effects / Cell Size / Cholangiocarcinoma - genetics / Cholangiocarcinoma - metabolism / Down-Regulation - drug effects / Down-Regulation - physiology / Drug Resistance, Multiple - drug effects / Drug Resistance, Neoplasm - drug effects / Gene Expression Regulation, Neoplastic - drug effects / Humans / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Original / Real-Time Polymerase Chain Reaction / RNA Interference / RNA, Small Interfering - pharmacology / Tissue Extracts - pharmacology / Wnt Signaling Pathway - drug effects / Wnt Signaling Pathway - physiology / Wnt3A Protein - pharmacology