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Notch pathway activation is associated with pancreatic cancer treatment failure

 Jin Young Lee  ;  Si Young Song  ;  Jeong Youp Park 
 PANCREATOLOGY, Vol.14(1) : 48-53, 2014 
Journal Title
Issue Date
Basic Helix-Loop-Helix Transcription Factors/biosynthesis ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Deoxycytidine/analogs & derivatives* ; Deoxycytidine/therapeutic use ; Homeodomain Proteins/biosynthesis ; Humans ; Neoplastic Stem Cells/physiology* ; Pancreatic Neoplasms/drug therapy* ; Prognosis ; Receptors, Notch/physiology* ; Transcription Factor HES-1 ; Treatment Failure
Cancer stem cell ; Notch ; Pancreatic cancer
BACKGROUND: Pancreatic cancer is resistant to conventional treatment. The aim of the study was to confirm the hypothesis that changes in cancer stem cells (CSCs) and developmental pathway after treatment was responsible for treatment failure in pancreatic cancer. METHODS: After recovery from a gemcitabine treatment, the percentage of pancreatic cancer CSCs and Notch pathway in BxPC3 and HPAC pancreatic cancer cell lines were analyzed by FACS (CD24 and CD44) and western blot (Notch1, Hes1, β-catenin, and pAKT). The effect of DAPT, a gamma-secretase inhibitor, was similarly investigated. The association between immunohistochemical expression of Hes1 and survival was analyzed. RESULTS: The percentage of CD24(+)CD44(+) cells was higher in gemcitabine-treated BxPC3 and HPAC cells than at pre-treatment. CD24(+)CD44(+) cells sorted from the gemcitabine-treated cell lines showed higher migration and invasion ability than CD24(-)CD44(-) or CD24(-)CD44(+) cells from the same cell lines. Western blot analysis showed an increased expression of Notch1 and Hes1 in gemcitabine-treated cell lines. The overall survival of pancreatic cancer patients with strong expression of Hes1 was shorter than that in patients with no or weak expression (11.1 vs. 21.6 months, P = 0.036). Treatment with DAPT reversed the increase in Hes1, β-catenin, and pAKT expression and the proportion of CD24(+)CD44(+) cells in gemcitabine-treated cell lines. The treatment also decreased migration and invasion ability. CONCLUSION: Our data suggested that an increase in CSCs and activation of the Notch pathway might contribute to the failure of treatment in pancreatic cancer. Notch pathway can be a potential target to overcome treatment failure.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Jeong Youp(박정엽) ORCID logo https://orcid.org/0000-0003-0110-8606
Song, Si Young(송시영) ORCID logo https://orcid.org/0000-0002-1417-4314
Lee, Jin Young(이진영)
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