Reference - Detail
|Author||Jinawath A, Akiyama Y, Sripa B, Yuasa Y.|
|Title||Dual blockade of the Hedgehog and ERK1/2 pathways coordinately decreases proliferation and survival of cholangiocarcinoma cells.|
|Journal||J. Cancer Res. Clin. Oncol.|
PURPOSE:The Hedgehog (Hh) and pERK1/2 pathways participate in the tumorigenesis of various tissues, but there has been no report on the involvement of these two pathways in cholangiocarcinoma (CCA). The aim of this study was to evaluate the effects of the Hh pathway inhibitor, cyclopamine, and MEK inhibitor, U0126, as a single agent or in combination on CCA cell proliferation and survival.
METHODS:Seven CCA cell lines were treated with cyclopamine and/or U0126, and cell proliferation was determined by WST-1 assay. The cell cycle was investigated by fluorescence-activated cell sorter analysis. The expression levels of several cell cycle-related genes were determined by western blot analyses.
RESULTS:Cyclopamine decreased cell proliferation and arrested the cell cycle at the G1 phase, while U0126 decreased the proliferation of CCA cells with KRAS mutation stronger than with wild-type KRAS. The combination of both inhibitors had an additive antiproliferative effect, particularly in cells with KRAS mutation, and induced caspase-dependent apoptosis in the CCA cells. The expression levels of cell cycle-related proteins that are targets of the two pathways, such as cyclin D1 and cyclin B1, were strongly decreased in some CCA cell lines after combined inhibitor treatment.
CONCLUSION:Our results suggest that the Hedgehog and ERK1/2 pathways are important for CCA cell proliferation, and simultaneous inhibition of the two pathways may lead to stronger decreases in cell growth and viability in a subset of CCA cases.
|MeSH||Apoptosis / drug effects Bile Duct Neoplasms / drug therapy Bile Duct Neoplasms / genetics* Bile Ducts, Intrahepatic Butadienes / pharmacology Cell Cycle / drug effects Cell Division / drug effects Cell Line, Tumor Cell Proliferation / drug effects* Cell Survival / drug effects* Cholangiocarcinoma / drug therapy Cholangiocarcinoma / genetics* Cyclin D1 / metabolism Drug Synergism Enzyme Inhibitors / pharmacology Flow Cytometry G1 Phase / drug effects Gene Expression Regulation, Neoplastic Hedgehog Proteins / antagonists & inhibitors Hedgehog Proteins / metabolism* Humans MAP Kinase Signaling System / drug effects Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors Mitogen-Activated Protein Kinase 1 / metabolism* Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors Mitogen-Activated Protein Kinase 3 / metabolism* Nitriles / pharmacology Veratrum Alkaloids / pharmacology|
|Human and Animal Cells|