These authors contributed equally to this work.
Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma
Article first published online: 6 AUG 2013
© 2013 Japanese Cancer Association
Volume 104, Issue 10, pages 1303–1308, October 2013
How to Cite
(Cancer Sci 2013; 104: 1303–1308
- Issue published online: 3 OCT 2013
- Article first published online: 6 AUG 2013
- Accepted manuscript online: 3 JUL 2013 11:36AM EST
- Manuscript Accepted: 22 JUN 2013
- Manuscript Revised: 17 JUN 2013
- Manuscript Received: 18 MAR 2013
- National Natural Science Foundation of China. Grant Numbers: 81101502, 81100194
- Excellent Youth Foundation of Fujian Province. Grant Number: 2009D016
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.