{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:39:53Z","timestamp":1790390393796,"version":"4.1.0"},"reference-count":195,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.<\/jats:p>","DOI":"10.3390\/cells9030614","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T10:46:08Z","timestamp":1583318768000},"page":"614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma"],"prefix":"10.3390","volume":"9","author":[{"given":"Hector","family":"Perez-Montoyo","sequence":"first","affiliation":[{"name":"Ability Pharmaceuticals, SL, Cerdanyola del Vall\u00e9s, 08290 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1002\/ar.20664","article-title":"Functional anatomy of normal bile ducts","volume":"291","author":"Strazzabosco","year":"2008","journal-title":"Anat. Rec."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1016\/S0140-6736(13)61903-0","article-title":"Cholangiocarcinoma","volume":"383","author":"Razumilava","year":"2014","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"419","DOI":"10.4254\/wjh.v2.i12.419","article-title":"Pathological classification of intrahepatic cholangiocarcinoma based on a new concept","volume":"2","author":"Nakanuma","year":"2010","journal-title":"World J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert consensus document: Cholangiocarcinoma: Current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)","volume":"13","author":"Banales","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1007\/s12094-015-1436-2","article-title":"Biliary tract cancers: SEOM clinical guidelines","volume":"17","author":"Benavides","year":"2015","journal-title":"Clin. Transl. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"v28","DOI":"10.1093\/annonc\/mdw324","article-title":"Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"27","author":"Valle","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_7","first-page":"42","article-title":"New insights into cholangiocarcinoma: Multiple stems and related cell lineages of origin","volume":"31","author":"Bragazzi","year":"2018","journal-title":"Ann. Gastroenterol. Hell. Soc. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00535-013-0894-y","article-title":"New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma","volume":"49","author":"Patel","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_9","first-page":"272","article-title":"Cholangiocarcinoma: Increasing burden of classifications","volume":"2","author":"Cardinale","year":"2013","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4251\/wjgo.v4.i5.94","article-title":"Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity","volume":"4","author":"Cardinale","year":"2012","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.jhep.2014.01.021","article-title":"Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma","volume":"60","author":"Bridgewater","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1159\/000360791","article-title":"Current diagnostic and management options in perihilar cholangiocarcinoma","volume":"89","author":"Rizvi","year":"2014","journal-title":"Digestion"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.5009\/gnl15568","article-title":"Cholangiocarcinoma: Current knowledge and new developments","volume":"11","author":"Blechacz","year":"2017","journal-title":"Gut Liver"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1634\/theoncologist.9-1-43","article-title":"Diagnosis and treatment of cholangiocarcinoma","volume":"9","author":"Anderson","year":"2004","journal-title":"Oncologist"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus Gemcitabine versus Gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/annonc\/mdt540","article-title":"Cisplatin and gemcitabine for advanced biliary tract cancer: A meta-analysis of two randomised trials","volume":"25","author":"Valle","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/path.2697","article-title":"Autophagy: Cellular and molecular mechanisms","volume":"221","author":"Glick","year":"2010","journal-title":"J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/15548627.2017.1378838","article-title":"Autophagy pathway: Cellular and molecular mechanisms","volume":"14","author":"Yu","year":"2018","journal-title":"Autophagy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nrd.2017.22","article-title":"Pharmacological modulation of autophagy: Therapeutic potential and persisting obstacles","volume":"16","author":"Galluzzi","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yun, C.W., and Lee, S.H. (2018). The roles of autophagy in cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113466"},{"key":"ref_21","first-page":"603980","article-title":"Tumor suppression and promotion by autophagy","volume":"2014","author":"Canales","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1080\/15548627.2016.1214778","article-title":"Autophagy induction for the treatment of cancer","volume":"12","author":"Pietrocola","year":"2016","journal-title":"Autophagy"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chude, C.I., and Amaravadi, R.K. (2017). Targeting autophagy in cancer: Update on clinical trials and novel inhibitors. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18061279"},{"key":"ref_24","first-page":"8023821","article-title":"Autophagy modulation in cancer: Current knowledge on action and therapy","volume":"2018","author":"Novak","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/446745a","article-title":"Cell biology: Autophagy and cancer","volume":"446","author":"Levine","year":"2007","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cudjoe, E.K., Kyte, S.L., Saleh, T., Landry, J.W., and Gewirtz, D.A. (2019). Autophagy inhibition and chemosensitization in cancer therapy. Targeting Cell Survival Pathways to Enhance Response to Chemotherapy, Elsevier.","DOI":"10.1016\/B978-0-12-813753-6.00012-3"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.4161\/auto.7.10.16610","article-title":"Prognostic significance of Beclin 1 in intrahepatic cholangiocellular carcinoma","volume":"7","author":"Dong","year":"2011","journal-title":"Autophagy"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, T.T., Cao, Q.H., Chen, M.Y., Xia, Q., Fan, X.J., Ma, X.K., Lin, Q., Jia, C.C., Dong, M., and Ruan, D.Y. (2013). Beclin 1 deficiency correlated with lymph node metastasis, predicts a distinct outcome in intrahepatic and extrahepatic cholangiocarcinoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080317"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.yexcr.2018.02.037","article-title":"MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2-STAT3 signaling axis","volume":"366","author":"Ma","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1159\/000487576","article-title":"FOXO1, a potential therapeutic target, regulates autophagic flux, oxidative stress, mitochondrial dysfunction, and apoptosis in human cholangiocarcinoma QBC939 cells","volume":"45","author":"He","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chen, L., Fu, H., Lu, T., Cai, J., Liu, W., Yao, J., Liang, J., Zhao, H., Zhang, J., and Zheng, J. (2019). An integrated nomogram combining clinical factors and microtubule-associated Protein 1 light chain 3B expression to predict postoperative prognosis in patients with intrahepatic cholangiocarcinomas. Cancer Res. Treat.","DOI":"10.4143\/crt.2019.423"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.jhep.2014.11.027","article-title":"Autophagy and senescence in fibrosing cholangiopathies","volume":"62","author":"Nakanuma","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Greer, S.U., Ogmundsdottir, M.H., Chen, J., Lau, B.T., Delacruz, R.G.C., Sandoval, I.T., Kristjansdottir, S., Jones, D.A., Haslem, D.S., and Romero, R. (2019). Genetic risk of cholangiocarcinoma is linked to the autophagy gene ATG7. BioRxiv, 836767.","DOI":"10.1101\/836767"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nrm4024","article-title":"Autophagy at the crossroads of catabolism and anabolism","volume":"16","author":"Kaur","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/cr.2013.168","article-title":"The machinery of macroautophagy","volume":"24","author":"Feng","year":"2014","journal-title":"Cell Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-cellbio-092910-154005","article-title":"The role of Atg proteins in autophagosome formation","volume":"27","author":"Mizushima","year":"2011","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5360","DOI":"10.1091\/mbc.e08-01-0080","article-title":"Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG","volume":"19","author":"Itakura","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/35044114","article-title":"A ubiquitin-like system mediates protein lipidation","volume":"408","author":"Ichimura","year":"2000","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1242\/jcs.196352","article-title":"New insights into autophagosome-lysosome fusion","volume":"130","author":"Nakamura","year":"2017","journal-title":"J. Cell Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1091\/mbc.e13-08-0447","article-title":"The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17","volume":"25","author":"Jiang","year":"2014","journal-title":"Mol. Biol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/ncb1740","article-title":"Beclin1-Binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking","volume":"10","author":"Liang","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1101\/gad.1565707","article-title":"Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis","volume":"21","author":"Patel","year":"2007","journal-title":"Genes Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"563","DOI":"10.4161\/auto.5830","article-title":"Tumor suppression by autophagy through the management of metabolic stress","volume":"4","author":"Jin","year":"2008","journal-title":"Autophagy"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB signaling: Navigating the network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"35243","DOI":"10.1074\/jbc.C100319200","article-title":"The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase\/protein kinase B pathway","volume":"276","author":"Arico","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/ncb1537","article-title":"The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis","volume":"9","author":"Liang","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1073\/pnas.1104361108","article-title":"Tumorigenesis in tuberous sclerosis complex is autophagy and p62\/sequestosome 1 (SQSTM1)-dependent","volume":"108","author":"Parkhitko","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/45257","article-title":"Induction of autophagy and inhibition of tumorigenesis by beclin 1","volume":"402","author":"Liang","year":"1999","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1056\/NEJMra1205406","article-title":"Mechanisms of disease: Autophagy in human health and disease","volume":"368","author":"Choi","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1101\/gad.1545107","article-title":"Autophagy suppresses tumor progression by limiting chromosomal instability","volume":"21","author":"Mathew","year":"2007","journal-title":"Genes Dev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.cell.2009.03.048","article-title":"Autophagy suppresses tumorigenesis through elimination of p62","volume":"137","author":"Mathew","year":"2009","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"417","DOI":"10.2174\/156652409788167131","article-title":"Regulation of autophagy through multiple independent hypoxic signaling pathways","volume":"9","author":"Rouschop","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"31582","DOI":"10.1074\/jbc.M506736200","article-title":"Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation","volume":"280","author":"Onodera","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1126\/science.1193497","article-title":"Autophagy and metabolism","volume":"330","author":"Rabinowitz","year":"2010","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.4161\/auto.26123","article-title":"Autophagy is required for mitochondrial function, lipid metabolism, growth, and fate of KRASG12D-driven lung tumors","volume":"9","author":"Guo","year":"2013","journal-title":"Autophagy"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1101\/gad.2016111","article-title":"Pancreatic cancers require autophagy for tumor growth","volume":"25","author":"Yang","year":"2011","journal-title":"Genes Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1091\/mbc.e10-06-0500","article-title":"Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation","volume":"22","author":"Lock","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1158\/2159-8290.CD-13-0841","article-title":"Autophagy-Dependent production of secreted factors facilitates oncogenic RAS-Driven invasion","volume":"4","author":"Lock","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Hern\u00e1ndez, M., Arias, A., Mart\u00ednez-Garc\u00eda, D., P\u00e9rez-Tom\u00e1s, R., Quesada, R., and Soto-Cerrato, V. (2019). Targeting autophagy for cancer treatment and tumor chemosensitization. Cancers, 11.","DOI":"10.3390\/cancers11101599"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1016\/j.bbamcr.2008.12.013","article-title":"Role and regulation of autophagy in cancer","volume":"1793","author":"Chen","year":"2009","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nrc.2017.53","article-title":"Targeting autophagy in cancer","volume":"17","author":"Levy","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"109415","DOI":"10.1016\/j.biopha.2019.109415","article-title":"Autophagy: A novel mechanism of chemoresistance in cancers","volume":"119","author":"Li","year":"2019","journal-title":"BioMed. Pharmacother."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"256","DOI":"10.4062\/biomolther.2012.20.3.256","article-title":"Tamoxifen resistance in breast cancer","volume":"20","author":"Chang","year":"2012","journal-title":"Biomol. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/sj.cdd.4401359","article-title":"Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells","volume":"11","author":"Kanzawa","year":"2004","journal-title":"Cell Death Differ."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1158\/0008-5472.CAN-03-2404","article-title":"Resveratrol-Induced autophagocytosis in ovarian cancer cells","volume":"64","author":"Opipari","year":"2004","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1038\/sj.onc.1208095","article-title":"Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3","volume":"24","author":"Kanzawa","year":"2005","journal-title":"Oncogene"},{"key":"ref_68","first-page":"1401","article-title":"Radiation-Induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells","volume":"26","author":"Ito","year":"2005","journal-title":"Int. J. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Labib, P.L., Goodchild, G., and Pereira, S.P. (2019). Molecular pathogenesis of cholangiocarcinoma. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5391-0"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Simile, M.M., Bagella, P., Vidili, G., Spanu, A., Manetti, R., Seddaiu, M.A., Babudieri, S., Madeddu, G., Serra, P.A., and Altana, M. (2019). Targeted therapies in cholangiocarcinoma: Emerging evidence from clinical trials. Medicina, 55.","DOI":"10.3390\/medicina55020042"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1053\/j.gastro.2013.01.001","article-title":"Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes","volume":"144","author":"Sia","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.18632\/oncotarget.1943","article-title":"Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups","volume":"5","author":"Simbolo","year":"2014","journal-title":"Oncotarget"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1002\/hep.26890","article-title":"Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma","volume":"59","author":"Arai","year":"2014","journal-title":"Hepatology"},{"key":"ref_74","first-page":"28","article-title":"The significance of genetics for cholangiocarcinoma development","volume":"1","author":"Maroni","year":"2013","journal-title":"Ann. Transl. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"407","DOI":"10.4251\/wjgo.v2.i11.407","article-title":"Intra-Hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors","volume":"2","author":"Cardinale","year":"2010","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_76","first-page":"58","article-title":"Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer","volume":"1","author":"Johnson","year":"2012","journal-title":"Transl. Gastrointest. Cancer"},{"key":"ref_77","first-page":"184","article-title":"Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism","volume":"60","author":"Jaiswal","year":"2000","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1053\/jhep.2002.31774","article-title":"COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells","volume":"35","author":"Nzeako","year":"2002","journal-title":"Hepatology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"109249","DOI":"10.1016\/j.biopha.2019.109249","article-title":"Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response","volume":"118","author":"Lin","year":"2019","journal-title":"BioMed. Pharmacother."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3740","DOI":"10.1158\/0008-5472.CAN-13-3182","article-title":"Autophagy inhibition by sustained overproduction of IL6 contributes to arsenic carcinogenesis","volume":"74","author":"Qi","year":"2014","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1080\/15548627.2017.1345412","article-title":"Inflammatory signaling cascades and autophagy in cancer","volume":"14","author":"Monkkonen","year":"2018","journal-title":"Autophagy"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Ngabire, D., and Kim, G.D. (2017). Autophagy and inflammatory response in the tumor microenvironment. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18092016"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1016\/j.humpath.2013.07.026","article-title":"The frequency of KRAS and BRAF mutations in intrahepatic cholangiocarcinomas and their correlation with clinical outcome","volume":"44","author":"Robertson","year":"2013","journal-title":"Hum. Pathol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1111\/j.1478-3231.2005.01106.x","article-title":"p53 mutations in human cholangiocarcinoma: A review","volume":"25","author":"Khan","year":"2005","journal-title":"Liver Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1158\/0008-5472.CAN-11-3596","article-title":"Kras G12D and p53 mutation cause primary intrahepatic cholangiocarcinoma","volume":"72","author":"Huang","year":"2012","journal-title":"Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.4161\/auto.20647","article-title":"Autophagy in intra-hepatic cholangiocarcinoma","volume":"8","author":"Huang","year":"2012","journal-title":"Autophagy"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1073\/pnas.1515617113","article-title":"Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy","volume":"113","author":"Eng","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1101\/gad.219642.113","article-title":"Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis","volume":"27","author":"Guo","year":"2013","journal-title":"Genes Dev."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Belmont, P.J., Jiang, P., McKee, T.D., Xie, T., Isaacson, J., Baryla, N.E., Roper, J., Sinnamon, M.J., Lee, N.V., and Kan, J.L. (2014). Resistance to dual blockade of the kinases PI3K and mTOR in KRAS-mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR. Sci. Signal., 7.","DOI":"10.1126\/scisignal.2005516"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"384","DOI":"10.4161\/auto.27320","article-title":"Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism","volume":"10","author":"Strohecker","year":"2014","journal-title":"Autophagy"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/s41568-019-0137-5","article-title":"Eliminating protective autophagy in KRAS-mutant cancers","volume":"19","year":"2019","journal-title":"Nat. Rev. Cancer."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.bbadis.2017.08.027","article-title":"Targeting cholangiocarcinoma","volume":"1864","author":"Mertens","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.3748\/wjg.14.2990","article-title":"c-Met targeted therapy of cholangiocarcinoma","volume":"14","author":"Socoteanu","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/bjc.2011.199","article-title":"Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma","volume":"105","author":"Miyamoto","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1111\/jphp.12140","article-title":"Inhibition of c-Met promoted apoptosis, autophagy and loss of the mitochondrial transmembrane potential in oridonin-induced A549 lung cancer cells","volume":"65","author":"Liu","year":"2013","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1158\/1078-0432.CCR-05-1692","article-title":"Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma","volume":"12","author":"Leone","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1053\/j.gastro.2005.10.010","article-title":"erbB-2\/neu transformed rat cholangiocytes recapitulate key cellular and molecular features of human bile duct cancer","volume":"129","author":"Lai","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Schmukler, E., and Pinkas-Kramarski, R. (2015). Inhibition of ErbB receptors and autophagy in cancer therapy. Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging 5, Elsevier Inc.","DOI":"10.1016\/B978-0-12-801033-4.00003-5"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1158\/2159-8290.CD-13-0050","article-title":"Identification of targetable FGFR gene fusions in diverse cancers","volume":"3","author":"Wu","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13046-017-0534-0","article-title":"FGF2\/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells","volume":"36","author":"Yuan","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbrc.2016.03.017","article-title":"FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell","volume":"474","author":"Chen","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1053\/hupa.2002.127444","article-title":"Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4\/Dpc4 in intrahepatic cholangiocarcinoma","volume":"33","author":"Kang","year":"2002","journal-title":"Hum. Pathol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3176","DOI":"10.1158\/1078-0432.CCR-17-3435","article-title":"SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy","volume":"24","author":"Wang","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s004320000194","article-title":"Multiple genetic alterations involved in the tumorigenesis of human cholangiocarcinoma: A molecular genetic and clinicopathological study","volume":"127","author":"Cong","year":"2001","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.humpath.2014.09.016","article-title":"Autophagy may occur at an early stage of cholangiocarcinogenesis via biliary intraepithelial neoplasia","volume":"46","author":"Sasaki","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/labinvest.2011.97","article-title":"Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma","volume":"91","author":"Hou","year":"2011","journal-title":"Lab. Investig."},{"key":"ref_107","first-page":"227","article-title":"Epigenetic alterations associated with cholangiocarcinoma","volume":"22","author":"Isomoto","year":"2009","journal-title":"Oncol. Rep."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.molcel.2016.12.027","article-title":"Epigenetic control of autophagy: Nuclear events gain more attention","volume":"65","author":"Baek","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1158\/0008-5472.CAN-12-2938","article-title":"HDAC6 inhibition restores ciliary expression and decreases tumor growth","volume":"73","author":"Gradilone","year":"2013","journal-title":"Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.ajpath.2013.11.027","article-title":"HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis","volume":"184","author":"Gradilone","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1038\/s41416-018-0232-5","article-title":"The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death","volume":"119","author":"Kaliszczak","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.surg.2011.07.038","article-title":"Role of histone deacetylase expression in intrahepatic cholangiocarcinoma","volume":"151","author":"Morine","year":"2012","journal-title":"Surgery"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1128\/MCB.01033-13","article-title":"Histone methylation keeps the brakes on autophagy","volume":"33","author":"Collins","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1634\/theoncologist.2011-0386","article-title":"Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping","volume":"17","author":"Borger","year":"2012","journal-title":"Oncologist"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1038\/onc.2012.315","article-title":"Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas","volume":"32","author":"Wang","year":"2013","journal-title":"Oncogene"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/bjc.2017.263","article-title":"Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A","volume":"117","author":"Rahim","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"167","DOI":"10.2217\/hep-2015-0003","article-title":"The role of miRNAs in cholangiocarcinoma","volume":"3","author":"Howell","year":"2016","journal-title":"Hepatic Oncol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1053\/j.gastro.2006.02.057","article-title":"Involvement of human Micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines","volume":"130","author":"Meng","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fonc.2017.00065","article-title":"Autophagy-Regulating microRNAs and Cancer","volume":"7","author":"Gozuacik","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1093\/carcin\/bgs266","article-title":"MicroRNA regulation of autophagy","volume":"33","author":"Frankel","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1093\/jb\/mvy047","article-title":"Involvement of partial EMT in cancer progression","volume":"164","author":"Saitoh","year":"2018","journal-title":"J. Biochem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/ncb3513","article-title":"The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer","volume":"19","author":"Krebs","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s12943-019-1030-2","article-title":"Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy","volume":"18","author":"Chen","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1002\/hep.29296","article-title":"aPKC-\u03b9\/P-Sp1\/Snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma","volume":"66","author":"Qian","year":"2017","journal-title":"Hepatology"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3164\/jcbn.14-8","article-title":"The inhibitory effect of heat treatment against epithelial-mesenchymal transition (EMT) in human pancreatic adenocarcinoma cell lines","volume":"55","author":"Ishikawa","year":"2014","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_126","first-page":"4913","article-title":"Autophagy may promote carcinoma cell invasion and correlate with poor prognosis in cholangiocarcinoma","volume":"7","author":"Nitta","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_127","first-page":"238","article-title":"Inhibition of Beclin 1 enhances apoptosis by H2O2 in glioma U251 cells","volume":"63","author":"Kong","year":"2011","journal-title":"Sheng Li Xue Bao"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1172\/JCI20039","article-title":"Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene","volume":"112","author":"Qu","year":"2003","journal-title":"J. Clin. Invest."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"G1202","DOI":"10.1152\/ajpgi.00104.2012","article-title":"The novel growth factor, progranulin, stimulates mouse cholangiocyte proliferation via sirtuin-1-mediated inactivation of FOXO1","volume":"303","author":"Frampton","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"e014961","DOI":"10.1136\/bmjopen-2016-014961","article-title":"Study protocol of a phase IB\/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours","volume":"7","author":"Molenaar","year":"2017","journal-title":"BMJ Open"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1124\/jpet.109.163337","article-title":"A novel sphingosine kinase inhibitor induces autophagy in tumor cells","volume":"333","author":"Beljanski","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"854","DOI":"10.3892\/ol.2014.1799","article-title":"Role of mTOR inhibitor in cholangiocarcinoma cell progression","volume":"7","author":"Moolthiya","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.1007\/s13277-013-0945-2","article-title":"Riggins & watcharin loilome. Increased activation of PI3K\/AKT signaling pathway is associated with cholangiocarcinoma metastasis and PI3K\/mTOR inhibition presents a possible therapeutic strategy","volume":"34","author":"Yothaisong","year":"2013","journal-title":"Tumor Biol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/bjc.2014.415","article-title":"Prognostic significance of epithelial-mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: Comprehensive immunohistochemical study using a tissue microarray","volume":"111","author":"Nitta","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Qu, X., Sheng, J., Shen, L., Su, J., Xu, Y., Xie, Q., Wu, Y., Zhang, X., and Sun, L. (2017). Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173712"},{"key":"ref_136","first-page":"3509","article-title":"Autophagy inhibitor chloroquine induces apoptosis of cholangiocarcinoma cells via endoplasmic reticulum stress","volume":"16","author":"Jia","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1007\/s10637-019-00741-3","article-title":"GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma","volume":"37","author":"Brun","year":"2019","journal-title":"Investig. New Drugs"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"3619","DOI":"10.18632\/oncotarget.23339","article-title":"Salinomycin inhibits cholangiocarcinoma growth by inhibition of autophagic flux","volume":"9","author":"Klose","year":"2018","journal-title":"Oncotarget"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Hong, Z.-F., Zhao, W.-X., Yin, Z.-Y., Xie, C.-R., Xu, Y.-P., Chi, X.-Q., Zhang, S., and Wang, X.-M. (2015). Capsaicin enhances the drug sensitivity of cholangiocarcinoma through the inhibition of chemotherapeutic-induced autophagy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121538"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.3892\/mmr.2016.5591","article-title":"Natural compound oblongifolin C inhibits autophagic flux, and induces apoptosis and mitochondrial dysfunction in human cholangiocarcinoma QBC939 cells","volume":"14","author":"Zhang","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.biopha.2018.12.051","article-title":"Mitochondrial division inhibitor-1 potentiates cisplatin-induced apoptosis via the mitochondrial death pathway in cholangiocarcinoma cells","volume":"111","author":"Tusskorn","year":"2019","journal-title":"BioMed. Pharmacother."},{"key":"ref_142","first-page":"4827","article-title":"Capsaicin induces apoptosis and autophagy in human melanoma cells","volume":"17","author":"Chu","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1158\/0008-5472.CAN-09-3537","article-title":"Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62\/SQSTM1 expression and AMPK activation","volume":"70","author":"Puissant","year":"2010","journal-title":"Cancer Res."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.canlet.2009.03.020","article-title":"Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells","volume":"282","author":"Signorelli","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Wang, Y., Jiang, W., Li, C., Xiong, X., Guo, H., Tian, Q., and Li, X. (2019). Autophagy suppression accelerates apoptosis induced by norcantharidin in cholangiocarcinoma. Pathol. Oncol. Res.","DOI":"10.1007\/s12253-019-00719-9"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"5538","DOI":"10.1002\/jcb.26723","article-title":"Compound C induces protective autophagy in human cholangiocarcinoma cells via Akt\/mTOR-independent pathway","volume":"119","author":"Zhao","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12951-015-0122-4","article-title":"Antitumor activity of vorinostat-incorporated nanoparticles against human cholangiocarcinoma cells","volume":"13","author":"Kwak","year":"2015","journal-title":"J. Nanobiotechnol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.bcp.2017.03.006","article-title":"Multifaceted anticancer activity of BH3 mimetics: Current evidence and future prospects","volume":"136","author":"Gonzalo","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"6748","DOI":"10.1158\/0008-5472.CAN-06-0169","article-title":"Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes","volume":"66","author":"Carracedo","year":"2006","journal-title":"Cancer Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.bcp.2018.02.007","article-title":"Autophagy inducers in cancer","volume":"153","author":"Russo","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_151","first-page":"1687","article-title":"Piperlongumine induces autophagy in biliary cancer cells via reactive oxygen species-activated Erk signaling pathway","volume":"44","author":"Chen","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.3389\/fphar.2019.01238","article-title":"Pterostilbene, an active constituent of blueberries, suppresses proliferation potential of human cholangiocarcinoma via enhancing the autophagic flux","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"12002","DOI":"10.1002\/jcb.28485","article-title":"Induction of cell-cycle arrest and apoptosis in human cholangiocarcinoma cells by pristimerin","volume":"120","author":"Sun","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1002\/mc.22893","article-title":"Dihydroartemisinin induces apoptosis and autophagy-dependent cell death in cholangiocarcinoma through a DAPK1-BECLIN1 pathway","volume":"57","author":"Thongchot","year":"2018","journal-title":"Mol. Carcinog."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/s10495-017-1422-y","article-title":"Piperlongumine induces G2\/M phase arrest and apoptosis in cholangiocarcinoma cells through the ROS-JNK-ERK signaling pathway","volume":"22","author":"Thongsom","year":"2017","journal-title":"Apoptosis"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.3892\/ol.2014.2499","article-title":"Decitabine inhibits the cell growth of cholangiocarcinoma in cultured cell lines and mouse xenografts","volume":"8","author":"Wang","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_157","first-page":"6028","article-title":"Phenformin inhibits cell proliferation and induces cell apoptosis and autophagy in cholangiocarcinoma","volume":"17","author":"Hu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Mu\u00f1oz-Guardiola, P., Casas, J., Meg\u00edas-Roda, E., Sol\u00e9, S., Perez-Montoyo, H., Yeste-Velasco, M., Erazo, T., Di\u00e9guez-Mart\u00ednez, N., Espinosa-Gil, S., and Mu\u00f1oz-Pinedoet, C. (2020). The anticancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy, in press.","DOI":"10.1080\/15548627.2020.1761651"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1186\/1476-4598-9-305","article-title":"Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation of tumor response to chemotherapy and radiation","volume":"9","author":"Gravina","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_160","unstructured":"Perez-Montoyo, H., Olaizola, P., Mu\u00f1oz-Guardiola, P., Megias-Roda, E., Sole, S., Gil, M., Vidal, L., Gascon, P., Jose, M., and Carles Domenech, L. (February, January 30). ABTL0812, a novel phase-2 clinical stage pro-autophagic anti-cancer compound with potential clinical activity in cholangiocarcinoma. Proceedings of the Cholangiocarcinoma Foundation Annual Conference, Salt Lake City, UT, USA."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1158\/1078-0432.CCR-15-1808","article-title":"The new antitumor drug ABTL0812 inhibits the Akt\/mTORC1 axis by upregulating Tribbles-3 pseudokinase","volume":"22","author":"Erazo","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"5834","DOI":"10.1128\/MCB.25.14.5834-5845.2005","article-title":"Regulation of mTOR and cell growth in response to energy stress by REDD1","volume":"25","author":"Sofer","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1016\/j.bbamcr.2013.06.028","article-title":"ER stress-induced cell death mechanisms","volume":"1833","author":"Sano","year":"2013","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2174\/1389203718666170406124547","article-title":"Mammalian pseudokinase TRIB3 in normal physiology and disease: Charting the progress in old and new avenues","volume":"18","author":"Ord","year":"2017","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.4161\/auto.5.7.9508","article-title":"TRB3 links ER stress to autophagy in cannabinoid anti-tumoral action","volume":"5","author":"Salazar","year":"2009","journal-title":"Autophagy"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/cdd.2014.133","article-title":"Loss of tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation","volume":"22","author":"Salazar","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/07357900903405934","article-title":"The dual effects of \u03949-tetrahydrocannabinol on cholangiocarcinoma cells: Anti-invasion activity at low concentration and apoptosis induction at high concentration","volume":"28","author":"Leelawat","year":"2010","journal-title":"Cancer Investig."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1093\/annonc\/mdw368.21","article-title":"Determination of recommended phase II dose of ABTL0812, a novel regulator of Akt\/mTOR axis, by pharmacokinetic-pharmacodynamic modelling","volume":"27","author":"Alfon","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ygyno.2019.03.002","article-title":"Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer","volume":"153","author":"Felip","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Plana, A., Fern\u00e1ndez-Nogueira, P., Mu\u00f1oz-Guardiola, P., Sol\u00e9-S\u00e1nchez, S., Meg\u00edas-Roda, E., P\u00e9rez-Montoyo, H., Jauregui, P., Yeste-Velasco, M., Erazo, M.G.T., and Ametller, E. (2020). The novel pro-autophagy anticancer drug ABTL0812 potentiates chemotherapy in adenocarcinoma and squamous non-small cell lung cancer. Int. J. Cancer.","DOI":"10.1002\/ijc.32865"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0168-8278(03)00029-1","article-title":"Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: A possible involvement of the ER stress pathway in hepatocarcinogenesis","volume":"38","author":"Shuda","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.canlet.2008.07.005","article-title":"Endoplasmic reticulum stress and autophagy as targets for cancer therapy","volume":"275","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"5873","DOI":"10.7314\/APJCP.2014.15.14.5873","article-title":"High expression of HIF-1\u03b1, BNIP3 and PI3KC3: Hypoxia-Induced autophagy predicts cholangiocarcinoma survival and metastasis","volume":"15","author":"Thongchot","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/cdd.2010.191","article-title":"The Beclin 1 network regulates autophagy and apoptosis","volume":"18","author":"Kang","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Lin, H.X., Qiu, H.J., Zeng, F., Rao, H.L., Yang, G.F., Kung, H.F., Zhu, X.F., Zeng, Y.X., Cai, M.Y., and Xie, D. (2013). Decreased expression of Beclin 1 correlates closely with Bcl-xL expression and poor prognosis of ovarian carcinoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060516"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"395","DOI":"10.4161\/auto.6.3.11303","article-title":"Elevated Beclin 1 expression is correlated with HIF-1\u03b1 in predicting poor prognosis of nasopharyngeal carcinoma","volume":"6","author":"Wan","year":"2010","journal-title":"Autophagy"},{"key":"ref_177","first-page":"2989","article-title":"The autophagy-related genes Beclin1 and LC3 in the prognosis of pancreatic cancer","volume":"12","author":"Cui","year":"2019","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"4583","DOI":"10.7314\/APJCP.2014.15.11.4583","article-title":"Prognostic significance of Beclin-1 expression in colorectal cancer: A meta-analysis","volume":"15","author":"Han","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"9167","DOI":"10.1158\/0008-5472.CAN-08-1573","article-title":"Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma","volume":"68","author":"Ding","year":"2008","journal-title":"Cancer Res."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/apm.12498","article-title":"Expression of Beclin-1, an autophagy-related marker, in chronic hepatitis and hepatocellular carcinoma and its relation with apoptotic markers","volume":"124","year":"2016","journal-title":"APMIS"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.1007\/s13277-015-3068-0","article-title":"Defective Beclin-1 and elevated hypoxia-inducible factor (HIF)-1\u03b1 expression are closely linked to tumorigenesis, differentiation, and progression of hepatocellular carcinoma","volume":"36","author":"Osman","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Bi, C., Liu, M., Rong, W., Wu, F., Zhang, Y., Lin, S., Liu, Y., Wu, J., and Wang, L. (2019). High Beclin-1 and ARID1A expression corelates with poor survival and high recurrence in intrahepatic cholangiocarcinoma: A histopathological retrospective study. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5429-3"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1080\/15548627.2016.1213927","article-title":"Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization","volume":"12","author":"Salanueva","year":"2016","journal-title":"Autophagy"},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Hirose, Y., Nagahashi, M., Katsuta, E., Yuza, K., Miura, K., Sakata, J., Kobayashi, T., Ichikawa, H., Shimada, Y., and Kameyama, H. (2018). Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-29144-9"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1007\/s13277-013-1049-8","article-title":"The role of beclin-1 expression in patients with gastric cancer: A meta-analysis","volume":"34","author":"Xia","year":"2013","journal-title":"Tumor Biol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.3748\/wjg.v13.i7.1129","article-title":"Mechanisms involved in ceramide-induced cell cycle arrest in human hepatocarcinoma cells","volume":"13","author":"Wang","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_187","first-page":"53","article-title":"Hypoxia enhances aggressiveness of cholangiocarcinoma cells","volume":"13","author":"Seubwai","year":"2012","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/mc.23050","article-title":"Autophagy facilitates the release of immunogenic signals following chemotherapy in 3D models of mesothelioma","volume":"58","author":"Follo","year":"2019","journal-title":"Mol. Carcinog."},{"key":"ref_189","first-page":"1","article-title":"Immunogenic cell death and immunotherapy of multiple myeloma","volume":"7","author":"Valle","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"4854","DOI":"10.1111\/jcmm.14356","article-title":"Immunogenic cell death in cancer therapy: Present and emerging inducers","volume":"23","author":"Zhou","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1200\/JCO.2019.37.15_suppl.4082","article-title":"Efficacy and safety of pembrolizumab in patients with PD-L1 positive advanced biliary tract cancer (BTC): A prospective cohort study","volume":"37","author":"Kang","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_192","first-page":"279ra41","article-title":"Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma","volume":"7","author":"Mok","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"e1577108","DOI":"10.1080\/2162402X.2019.1577108","article-title":"Triple combination immunotherapy with GVAX, anti-PD-1 monoclonal antibody, and agonist anti-OX40 monoclonal antibody is highly effective against murine intracranial glioma","volume":"8","author":"Jahan","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1111\/pcmr.12383","article-title":"Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab","volume":"28","author":"Minor","year":"2015","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1475-2867-13-26","article-title":"Beclin1 inhibition promotes autophagy and decreases gemcitabine-induced apoptosis in Miapaca2 pancreatic cancer cells","volume":"13","author":"Li","year":"2013","journal-title":"Cancer Cell Int."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/614\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:03:58Z","timestamp":1760173438000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/614"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,4]]},"references-count":195,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["cells9030614"],"URL":"https:\/\/doi.org\/10.3390\/cells9030614","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202002.0015.v1","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,4]]}}}