Abstract
Hedgehog signaling plays critical roles in drug resistance of PDAC. We demonstrate that SHH is highly expressed in PDAC patients and cell lines. SHH signaling protects PDAC cells against gemcitabine induced apoptosis, because either over-expression or knockdown of SHH in PDAC cells affects the sensitivity to gemcitabine. Mechanistic studies show that ABCB2 serves as the downstream target of SHH signaling, leading to the drug resistance of PDAC cells. Combinational treatments with gemcitabine and cyclopamine yield synergistic antitumor effects in vitro and in vivo. Our study suggests that inhibiting SHH signaling or targeting ABCB2 gene improves the efficacy of chemotherapy in patients with PDAC.
Copyright © 2013. Published by Elsevier Ireland Ltd.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B, Member 2
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism*
-
Adenocarcinoma / drug therapy
-
Adenocarcinoma / metabolism*
-
Adenocarcinoma / pathology
-
Animals
-
Antimetabolites, Antineoplastic / pharmacology
-
Cell Line, Tumor
-
Deoxycytidine / analogs & derivatives
-
Deoxycytidine / pharmacology
-
Drug Resistance, Neoplasm*
-
Female
-
Gemcitabine
-
Gene Expression Regulation, Neoplastic
-
Hedgehog Proteins / genetics
-
Hedgehog Proteins / metabolism*
-
Humans
-
Mice
-
Mice, Nude
-
Pancreatic Neoplasms / drug therapy
-
Pancreatic Neoplasms / metabolism*
-
Pancreatic Neoplasms / pathology
-
Signal Transduction
-
Xenograft Model Antitumor Assays
Substances
-
ATP Binding Cassette Transporter, Subfamily B, Member 2
-
ATP-Binding Cassette Transporters
-
Antimetabolites, Antineoplastic
-
DHH protein, human
-
Hedgehog Proteins
-
IHH protein, human
-
SHH protein, human
-
TAP1 protein, human
-
Deoxycytidine
-
Gemcitabine