1. Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation
- Author
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Ruth Joplin, A. Furlanetto, Mario Strazzabosco, Annarosa Floreani, Marco Massani, Marta Vismara, Stuart Morton, Massimiliano Cadamuro, Luca Fabris, Tommaso Stecca, Nicolò Bassi, Simone Brivio, Morton, S, Cadamuro, M, Brivio, S, Vismara, M, Stecca, T, Massani, M, Bassi, N, Furlanetto, A, Joplin, R, Floreani, A, Fabris, L, and Strazzabosco, M
- Subjects
Leukemia Inhibitory Factor Receptor alpha Subunit ,medicine.medical_treatment ,Leukemia inhibitory factor receptor ,Apoptosis ,Deoxycytidine ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,MED/12 - GASTROENTEROLOGIA ,phosphatidylinositol-3 kinase ,STAT3 ,reproductive and urinary physiology ,0303 health sciences ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,chemoresistance ,3. Good health ,Gene Expression Regulation, Neoplastic ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,embryonic structures ,RNA Interference ,cholangiocarcinoma ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,Research Paper ,endocrine system ,Blotting, Western ,Antineoplastic Agents ,03 medical and health sciences ,Paracrine signalling ,Cell Line, Tumor ,medicine ,Humans ,Autocrine signalling ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,urogenital system ,Mcl-1 ,Gemcitabine ,leukemia inhibitory factor ,Bile Duct Neoplasms ,Microscopy, Fluorescence ,Immunology ,Cancer research ,biology.protein ,Myeloid Cell Leukemia Sequence 1 Protein ,Cisplatin ,Leukemia inhibitory factor ,Proto-Oncogene Proteins c-akt - 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.
- Published
- 2015