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Local Delivery of Gemcitabine Inhibits Pancreatic and Cholangiocarcinoma Tumor Growth by Promoting Epidermal Growth Factor Receptor Degradation

Authors
 Sung Ill Jang  ;  Sungsoon Fang  ;  Yi-Yong Baek  ;  Don Haeng Lee  ;  Kun Na  ;  Su Yeon Lee  ;  Dong Ki Lee 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.21(5) : E1605, 2020 
Journal Title
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 
Issue Date
2020
Keywords
EGFR ; angiogenesis ; biliary duct carcinoma ; drug-eluting stent ; gemcitabine ; pancreatic cancer
Abstract
Gemcitabine is clinically used to treat certain types of cancers, including pancreatic and biliary cancer. We investigated the signal transduction pathways underlying the local antitumor effects of gemcitabine-eluting membranes (GEMs) implanted in pancreatic/biliary tumor-bearing nude mice. Here, we report that GEMs increased the E3 ubiquitin ligase c-CBL protein level, leading to degradation of epidermal growth factor receptor (EGFR) in SCK and PANC-1 cells. GEMs decreased the RAS and PI3K protein levels, leading to a reduction in the protein levels of active forms of downstream signaling molecules, including PDK, AKT, and GSK3β. GEM reduced proliferation of cancer cells by upregulating cell cycle arrest proteins, particularly p53 and p21, and downregulating cyclin D1 and cyclin B. Moreover, GEMs reduced the levels of proangiogenic factors, including VEGF, VEGFR2, CD31, and HIF-1α, and inhibited tumor cell migration and invasion by inducing the expression of E-cadherin and reducing that of N-cadherin, snail, and vimentin. We demonstrated that local delivery of gemcitabine using GEM implants inhibited tumor cell growth by promoting c-CBL-mediated degradation of EGFR and inhibiting the proliferation, angiogenesis, and epithelial-mesenchymal transition of pancreatic/biliary tumors. Use of gemcitabine-eluting stents can improve stent patency by inhibiting the ingrowth of malignant biliary obstructions.
Files in This Item:
T202000622.pdf Download
DOI
10.3390/ijms21051605
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Dong Ki(이동기) ORCID logo https://orcid.org/0000-0002-0048-9112
Jang, Sung Ill(장성일) ORCID logo https://orcid.org/0000-0003-4937-6167
Fang, Sungsoon(황성순) ORCID logo https://orcid.org/0000-0003-0201-5567
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175539
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