Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors

Jalaj Gupta; Ana Igea; Marilena Papaioannou; Pedro Pablo Lopez-Casas; Elisabet Llonch; Manuel Hidalgo; Vassilis G Gorgoulis; Angel R Nebreda

doi:10.18632/oncotarget.3816

Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors

Oncotarget. 2015 Apr 20;6(11):8539-51. doi: 10.18632/oncotarget.3816.

Authors

Jalaj Gupta¹, Ana Igea¹, Marilena Papaioannou², Pedro Pablo Lopez-Casas³, Elisabet Llonch¹, Manuel Hidalgo³, Vassilis G Gorgoulis^{2

4

5}, Angel R Nebreda^{1

6}

Affiliations

¹ Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
² Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
³ Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁴ Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
⁵ Faculty Institute of Cancer Sciences, University of Manchester, Manchester, UK.
⁶ Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

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.

Keywords: colon cancer; mouse xenograft; p38 MAPK; therapy.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / enzymology
Adenocarcinoma / pathology*
Adenocarcinoma / secondary
Animals
Antineoplastic Agents / therapeutic use*
Benzamides / therapeutic use*
Carcinoma, Neuroendocrine / drug therapy
Carcinoma, Neuroendocrine / enzymology
Carcinoma, Neuroendocrine / genetics
Carcinoma, Neuroendocrine / pathology*
Cell Differentiation
Colonic Neoplasms / drug therapy
Colonic Neoplasms / enzymology
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology*
Cytokines / metabolism
Genes, ras
Humans
Liver Neoplasms / enzymology
Liver Neoplasms / secondary
MAP Kinase Signaling System / drug effects*
MAP Kinase Signaling System / physiology
Mice
Mice, Nude
Mutation
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / physiology
Neoplasm Staging
Protein Kinase Inhibitors / therapeutic use*
Pyridones / therapeutic use*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
p38 Mitogen-Activated Protein Kinases / physiology

Substances

Antineoplastic Agents
Benzamides
Cytokines
Neoplasm Proteins
PH 797804
Protein Kinase Inhibitors
Pyridones
p38 Mitogen-Activated Protein Kinases