{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T12:40:30Z","timestamp":1784292030076,"version":"3.55.0"},"reference-count":85,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["BFU2016-79259-R"],"award-info":[{"award-number":["BFU2016-79259-R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["EQC2018-004646-P"],"award-info":[{"award-number":["EQC2018-004646-P"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Junta de Extremadura-FEDER","award":["GR18070"],"award-info":[{"award-number":["GR18070"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM\u20131 \u00b5M) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2\u03b1 and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44\/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of \u03b1-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.<\/jats:p>","DOI":"10.3390\/ijms22115555","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T12:38:01Z","timestamp":1621859881000},"page":"5555","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-7904","authenticated-orcid":false,"given":"Matias","family":"Estaras","sequence":"first","affiliation":[{"name":"Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5963-3943","authenticated-orcid":false,"given":"Manuel R.","family":"Gonzalez-Portillo","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Fernandez-Bermejo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8699-8606","authenticated-orcid":false,"given":"Jose M.","family":"Mateos","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Vara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, San Pedro de Alcantara Hospital, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-5306","authenticated-orcid":false,"given":"Gerardo","family":"Blanco-Fernandez","sequence":"additional","affiliation":[{"name":"Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, University Hospital, 06080 Badajoz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Lopez-Guerra","sequence":"additional","affiliation":[{"name":"Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, University Hospital, 06080 Badajoz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Roncero","sequence":"additional","affiliation":[{"name":"Unit of Histology and Pathological Anatomy, Veterinary Faculty, University of Extremadura, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8687-2445","authenticated-orcid":false,"given":"Gines M.","family":"Salido","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8380-0270","authenticated-orcid":false,"given":"Antonio","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003 Caceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.7150\/jca.38616","article-title":"Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer","volume":"11","author":"Jin","year":"2020","journal-title":"J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-3-030-37184-5_5","article-title":"Pancreatic Stellate Cells: The Key Orchestrator of The Pancreatic Tumor Microenvironment","volume":"1234","author":"Thomas","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11008","DOI":"10.1021\/acsnano.9b02395","article-title":"Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors","volume":"13","author":"Zinger","year":"2019","journal-title":"ACS Nano"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13713","DOI":"10.1038\/s41598-018-32054-5","article-title":"Stabilization of HIF-2alpha impacts pancreas growth","volume":"8","author":"Rojas","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.canlet.2019.10.034","article-title":"Imatinib revives the therapeutic potential of metformin on ewing sarcoma by attenuating tumor hypoxic response and inhibiting convergent signaling pathways","volume":"469","author":"Nan","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/boc.202000020","article-title":"Pancreatic stellate cells exhibit adaptation to oxidative stress evoked by hypoxia","volume":"112","author":"Estaras","year":"2020","journal-title":"Biol. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1593\/neo.81618","article-title":"Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma","volume":"11","author":"Erkan","year":"2009","journal-title":"Neoplasia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.freeradbiomed.2018.03.042","article-title":"Hypoxia, oxidative stress and inflammation","volume":"125","author":"McGarry","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1002\/ijc.28583","article-title":"Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-kappaB downregulation","volume":"134","author":"Liu","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Porcelli, L., Iacobazzi, R.M., Di Fonte, R., Serrati, S., Intini, A., Solimando, A.G., Brunetti, O., Calabrese, A., Leonetti, F., and Azzariti, A. (2019). CAFs and TGF-beta Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine\/Nabpaclitaxel in Pancreatic Cancer. Cancers (Basel), 11.","DOI":"10.3390\/cancers11030330"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhang, J.J., Meng, X., Li, Y., Zhou, Y., Xu, D.P., Li, S., and Li, H.B. (2017). Effects of Melatonin on Liver Injuries and Diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040673"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12868-019-0545-1","article-title":"Inhibition of autophagy triggers melatonin-induced apoptosis in glioblastoma cells","volume":"20","author":"Zhou","year":"2019","journal-title":"BMC Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.omtn.2019.12.019","article-title":"Melatonin Regulates Breast Cancer Progression by the lnc010561\/miR-30\/FKBP3 Axis","volume":"19","author":"Liu","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1002\/jcp.29049","article-title":"Melatonin: An important anticancer agent in colorectal cancer","volume":"235","author":"Mohammadzadeh","year":"2020","journal-title":"J. Cell Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/tox.22674","article-title":"Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, beta-catenin, and Twist pathways","volume":"34","author":"Yang","year":"2019","journal-title":"Environ. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chen, C.C., Chen, C.Y., Wang, S.H., Yeh, C.T., Su, S.C., Ueng, S.H., Chuang, W.Y., Hsueh, C., and Wang, T.H. (2018). Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair. Cancers (Basel), 10.","DOI":"10.3390\/cancers10090320"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.3892\/or.2016.5100","article-title":"Melatonin induces cell apoptosis in Mia PaCa-2 cells via the suppression of nuclear factor-kappaB and activation of ERK and JNK: A novel therapeutic implication for pancreatic cancer","volume":"36","author":"Li","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s13105-019-00671-x","article-title":"Melatonin induces reactive oxygen species generation and changes in glutathione levels and reduces viability in human pancreatic stellate cells","volume":"75","author":"Estaras","year":"2019","journal-title":"J. Physiol. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s13105-020-00740-6","article-title":"Melatonin modulates proliferation of pancreatic stellate cells through caspase-3 activation and changes in cyclin A and D expression","volume":"76","author":"Estaras","year":"2020","journal-title":"J. Physiol. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6352","DOI":"10.1038\/s41598-020-63433-6","article-title":"Melatonin modulates red-ox state and decreases viability of rat pancreatic stellate cells","volume":"10","author":"Gonzalez","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s10565-015-9297-6","article-title":"Melatonin induces calcium mobilization and influences cell proliferation independently of MT1\/MT2 receptor activation in rat pancreatic stellate cells","volume":"31","author":"Ruy","year":"2015","journal-title":"Cell Biol. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1111\/j.1600-079X.2010.00834.x","article-title":"Melatonin reduces pancreatic tumor cell viability by altering mitochondrial physiology","volume":"50","author":"Gonzalez","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_23","first-page":"197","article-title":"Thapsigargin induces apoptosis in SH-SY5Y neuroblastoma cells and cerebrocortical cultures","volume":"43","author":"Nath","year":"1997","journal-title":"Biochem. Mol. Biol. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.phrs.2016.03.012","article-title":"Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs","volume":"107","author":"Roskoski","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Thakur, N., Kumari, S., and Mehrotra, R. (2018). Association between Cyclin D1 G870A (rs9344) polymorphism and cancer risk in Indian population: Meta-analysis and trial sequential analysis. Biosci. Rep., 38.","DOI":"10.1042\/BSR20180694"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1007\/s00262-017-2019-6","article-title":"Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: A promising opportunity for cancer immunotherapy","volume":"66","author":"Mohamed","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/jpi.12264","article-title":"Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis","volume":"59","author":"Fernandez","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.ymeth.2004.10.010","article-title":"The ER chaperone and signaling regulator GRP78\/BiP as a monitor of endoplasmic reticulum stress","volume":"35","author":"Lee","year":"2005","journal-title":"Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"727","DOI":"10.3233\/JAD-2012-111898","article-title":"Bip enhanced the association of GSK-3beta with tau during ER stress both in vivo and in vitro","volume":"29","author":"Liu","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_30","first-page":"423","article-title":"Melatonin influences pancreatic cancerogenesis","volume":"29","author":"Jaworek","year":"2014","journal-title":"Histol. Histopathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/jnr.20471","article-title":"Caspases-2, -3, and -7 are involved in thapsigargin-induced apoptosis of SH-SY5Y neuroblastoma cells","volume":"80","author":"Dahmer","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chen, C., Nelson, L.J., Avila, M.A., and Cubero, F.J. (2019). Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link. Cells, 8.","DOI":"10.3390\/cells8101172"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1136\/gut.2005.064543","article-title":"Vitamin A inhibits pancreatic stellate cell activation: Implications for treatment of pancreatic fibrosis","volume":"55","author":"McCarroll","year":"2006","journal-title":"Gut"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/bs.pmbts.2017.03.004","article-title":"The Roles of Matrix Metalloproteinases in Pancreatic Cancer","volume":"148","author":"Knapinska","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.amjms.2018.10.001","article-title":"Pancreatic Stellate Cells Activation and Matrix Metallopeptidase 2 Expression Correlate With Lymph Node Metastasis in Pancreatic Carcinoma","volume":"357","author":"Li","year":"2019","journal-title":"Am. J. Med. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12943-018-0927-5","article-title":"Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis","volume":"18","author":"Thomas","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.canlet.2019.07.015","article-title":"YAP1-mediated pancreatic stellate cell activation inhibits pancreatic cancer cell proliferation","volume":"462","author":"Xiao","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.7150\/jca.30235","article-title":"PSME3 Promotes TGFB1 Secretion by Pancreatic Cancer Cells to Induce Pancreatic Stellate Cell Proliferation","volume":"10","author":"Yu","year":"2019","journal-title":"J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1586\/17474124.2016.1117386","article-title":"The role of hypoxia in pancreatic cancer: A potential therapeutic target?","volume":"10","author":"Erkan","year":"2016","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.ajpath.2016.09.012","article-title":"Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration","volume":"187","author":"Birtolo","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10","DOI":"10.4292\/wjgpt.v8.i1.10","article-title":"Pathogenic mechanisms of pancreatitis","volume":"8","author":"Manohar","year":"2017","journal-title":"World J. Gastrointest Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1042\/CS20180945","article-title":"Melatonin suppresses lung cancer metastasis by inhibition of epithelial-mesenchymal transition through targeting to Twist","volume":"133","author":"Chao","year":"2019","journal-title":"Clin. Sci. (Lond.)"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S324","DOI":"10.4103\/0973-1482.235349","article-title":"Synergistic effect of thymoquinone and melatonin against breast cancer implanted in mice","volume":"14","author":"Odeh","year":"2018","journal-title":"J. Cancer Res. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.3390\/ijms19092687","article-title":"Melatonin Inhibits the Progression of Hepatocellular Carcinoma through MicroRNA Let7i-3p Mediated RAF1 Reduction","volume":"19","author":"Wang","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5372","DOI":"10.1002\/jcp.27372","article-title":"Melatonin and pancreatic cancer: Current knowledge and future perspectives","volume":"234","author":"Tamtaji","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6190","DOI":"10.1158\/0008-5472.CAN-19-1116","article-title":"Parallel Signaling through IRE1alpha and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival","volume":"79","author":"Moore","year":"2019","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1111\/febs.13598","article-title":"Cell death induced by endoplasmic reticulum stress","volume":"283","author":"Iurlaro","year":"2016","journal-title":"FEBS J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2594703","DOI":"10.1155\/2016\/2594703","article-title":"Melatonin-Mediated Intracellular Insulin during 2-Deoxy-d-glucose Treatment Is Reduced through Autophagy and EDC3 Protein in Insulinoma INS-1E Cells","volume":"2016","author":"Kim","year":"2016","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Moreira, A.J., Ordonez, R., Cerski, C.T., Picada, J.N., Garcia-Palomo, A., Marroni, N.P., Mauriz, J.L., and Gonzalez-Gallego, J. (2015). Melatonin Activates Endoplasmic Reticulum Stress and Apoptosis in Rats with Diethylnitrosamine-Induced Hepatocarcinogenesis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144517"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3951","DOI":"10.21873\/anticanres.12681","article-title":"Melatonin Promotes Apoptosis of Colorectal Cancer Cells via Superoxide-mediated ER Stress by Inhibiting Cellular Prion Protein Expression","volume":"38","author":"Yun","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/path.5320","article-title":"The integrin alphavbeta6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy","volume":"249","author":"Reader","year":"2019","journal-title":"J. Pathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrm3270","article-title":"The unfolded protein response: Controlling cell fate decisions under ER stress and beyond","volume":"13","author":"Hetz","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"109752","DOI":"10.1016\/j.biopha.2019.109752","article-title":"Oleanolic acid inhibits mouse spinal cord injury through suppressing inflammation and apoptosis via the blockage of p38 and JNK MAPKs","volume":"123","author":"Wang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/j.1600-079X.2011.00910.x","article-title":"Melatonin modulation of intracellular signaling pathways in hepatocarcinoma HepG2 cell line: Role of the MT1 receptor","volume":"51","author":"Piva","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/jcp.28993","article-title":"TRB3 interacts with ERK and JNK and contributes to the proliferation, apoptosis, and migration of lung adenocarcinoma cells","volume":"235","author":"Cao","year":"2020","journal-title":"J. Cell Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.canlet.2017.06.034","article-title":"Secretory Stanniocalcin 1 promotes metastasis of hepatocellular carcinoma through activation of JNK signaling pathway","volume":"403","author":"Chan","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1097\/MPA.0000000000001055","article-title":"Activating P2X7 Receptors Increases Proliferation of Human Pancreatic Cancer Cells via ERK1\/2 and JNK","volume":"47","author":"Choi","year":"2018","journal-title":"Pancreas"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10616-018-0277-6","article-title":"Vitronectin, fibronectin and epidermal growth factor induce proliferation via the JNK and ERK pathways in insulinoma INS-1 cells","volume":"71","author":"Bolkent","year":"2019","journal-title":"Cytotechnology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"50057","DOI":"10.18632\/oncotarget.10315","article-title":"Extracellular translationally controlled tumor protein promotes colorectal cancer invasion and metastasis through Cdc42\/JNK\/ MMP9 signaling","volume":"7","author":"Xiao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00418-012-0967-7","article-title":"XBP1S protects cells from ER stress-induced apoptosis through Erk1\/2 signaling pathway involving CHOP","volume":"138","author":"Guo","year":"2012","journal-title":"Histochem. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"919","DOI":"10.4093\/dmj.2019.0181","article-title":"Hypoxia Increases beta-Cell Death by Activating Pancreatic Stellate Cells within the Islet","volume":"44","author":"Kim","year":"2020","journal-title":"Diabetes Metab. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5615","DOI":"10.1111\/jcmm.15221","article-title":"Melatonin ameliorates renal fibroblast-myofibroblast transdifferentiation and renal fibrosis through miR-21-5p regulation","volume":"24","author":"Li","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1159\/000493380","article-title":"Melatonin Attenuates Endothelial-to-Mesenchymal Transition of Glomerular Endothelial Cells via Regulating miR-497\/ROCK in Diabetic Nephropathy","volume":"43","author":"Liu","year":"2018","journal-title":"Kidney Blood Press Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.trsl.2014.10.003","article-title":"Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice","volume":"165","author":"Crespo","year":"2015","journal-title":"Transl. Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Zhao, H., Wu, Q.Q., Cao, L.F., Qing, H.Y., Zhang, C., Chen, Y.H., Wang, H., Liu, R.Y., and Xu, D.X. (2014). Melatonin inhibits endoplasmic reticulum stress and epithelial-mesenchymal transition during bleomycin-induced pulmonary fibrosis in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097266"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"32154","DOI":"10.18632\/oncotarget.5168","article-title":"Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer","volume":"6","author":"Kong","year":"2015","journal-title":"Oncotarget"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s12253-016-0059-4","article-title":"Strong Correlation Between mRNA Expression Levels of HIF-2alpha, VEGFR1, VEGFR2 and MMP2 in Laryngeal Carcinoma","volume":"22","author":"Popov","year":"2016","journal-title":"Pathol. Oncol. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1742-4658.2010.07919.x","article-title":"Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting","volume":"278","author":"Gialeli","year":"2011","journal-title":"FEBS J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1007\/s13277-013-0842-8","article-title":"Matrix metalloproteinases in cancer: Their value as diagnostic and prognostic markers and therapeutic targets","volume":"34","author":"Winberg","year":"2013","journal-title":"Tumour. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1007\/s00424-017-2057-0","article-title":"TRPC6 channels modulate the response of pancreatic stellate cells to hypoxia","volume":"469","author":"Nielsen","year":"2017","journal-title":"Pflugers Arch."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1007\/s00018-014-1579-2","article-title":"Extrapineal melatonin: Sources, regulation, and potential functions","volume":"71","author":"Escames","year":"2014","journal-title":"Cell Mol. Life Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.3748\/wjg.v17.i34.3888","article-title":"Distribution, function and physiological role of melatonin in the lower gut","volume":"17","author":"Chen","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_75","first-page":"1429","article-title":"Melatonin-synthesizing enzymes and melatonin receptor in rat thyroid cells","volume":"27","author":"Utrilla","year":"2012","journal-title":"Histol. Histopathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/S1357-2725(01)00138-8","article-title":"Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria","volume":"34","author":"Martin","year":"2002","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.freeradbiomed.2015.06.033","article-title":"Melatonin induces the expression of Nrf2-regulated antioxidant enzymes via PKC and Ca2+ influx activation in mouse pancreatic acinar cells","volume":"87","author":"Bolanos","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s13105-013-0267-2","article-title":"Melatonin modulates Ca2+ mobilization and amylase release in response to cholecystokinin octapeptide in mouse pancreatic acinar cells","volume":"69","author":"Ruy","year":"2013","journal-title":"J. Physiol. Biochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11010-014-2174-4","article-title":"Pharmacological dose of melatonin reduces cytosolic calcium load in response to cholecystokinin in mouse pancreatic acinar cells","volume":"397","author":"Ruy","year":"2014","journal-title":"Mol. Cell Biochem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cmet.2016.09.009","article-title":"Reciprocal Regulation between the Circadian Clock and Hypoxia Signaling at the Genome Level in Mammals","volume":"25","author":"Wu","year":"2017","journal-title":"Cell Metab."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.cell.2018.05.009","article-title":"Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR","volume":"174","author":"Walton","year":"2018","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1016\/j.bbagen.2014.10.025","article-title":"The circadian clock and hypoxia in tumor cell de-differentiation and metastasis","volume":"1850","author":"Jensen","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Argentiero, A., De Summa, S., Di Fonte, R., Iacobazzi, R.M., Porcelli, L., Da Via, M., Brunetti, O., Azzariti, A., Silvestris, N., and Solimando, A.G. (2019). Gene Expression Comparison between the Lymph Node-Positive and -Negative Reveals a Peculiar Immune Microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study. Cancers (Basel), 11.","DOI":"10.20944\/preprints201906.0228.v1"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"20563","DOI":"10.18632\/oncotarget.25003","article-title":"Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma","volume":"9","author":"Lamanuzzi","year":"2018","journal-title":"Oncotarget"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. 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