Please use this identifier to cite or link to this item:
|Title:||Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation||Authors:||Morton, Stuart Duncan
Joplin, Ruth Elizabeth
|Keywords:||Mcl-1;chemoresistance;cholangiocarcinoma;leukemia inhibitory factor;phosphatidylinositol-3 kinase||Keywords Plus:||GROWTH-FACTOR;CARCINOMA-CELLS;CANCER;EXPRESSION;LIF;INTERLEUKIN-6;MANAGEMENT;DIAGNOSIS;SURVIVAL;PATHWAY||Mesh headings:||Antineoplastic Agents;Apoptosis;Leukemia Inhibitory Factor;Myeloid Cell Leukemia Sequence 1 Protein;Phosphatidylinositol 3-Kinases;Proto-Oncogene Proteins c-akt||Secondary Mesh headings:||Bile Duct Neoplasms;Blotting, Western;Cell Line, Tumor;Cholangiocarcinoma;Cisplatin;Deoxycytidine;Gene Expression Regulation, Neoplastic;Humans;Leukemia Inhibitory Factor Receptor alpha Subunit;Microscopy, Fluorescence;RNA Interference;Reverse Transcriptase Polymerase Chain Reaction;Signal Transduction||Issue Date:||22-Sep-2015||Publisher:||IMPACT JOURNALS LLC||Journal:||Oncotarget||Abstract:||
Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation.Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis.In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy.
|Appears in Collections:||Articles|
Show full item record
checked on Dec 5, 2021
checked on Sep 1, 2020
WEB OF SCIENCETM
checked on Dec 3, 2021
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.