title: Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors.
abstract: Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Jalaj
authors.initials: J
authors.lastname: Gupta
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Igea
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Marilena
authors.initials: M
authors.lastname: Papaioannou
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Pedro Pablo
authors.initials: PP
authors.lastname: Lopez-Casas
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Llonch
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.|Biomedical Research Foundation of the Academy of Athens, Athens, Greece.|Faculty Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000556:secondary; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D009363:Neoplasm Proteins; C542398:PH 797804; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D048051:p38 Mitogen-Activated Protein Kinases
keywords: colon cancer; mouse xenograft; p38 MAPK; therapy