Oncotarget

Priority Research Papers:

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 and Angel R. Nebreda _

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Oncotarget. 2015; 6:8539-8551. https://doi.org/10.18632/oncotarget.3816

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Abstract

Jalaj Gupta1,*, Ana Igea1,*, Marilena Papaioannou2, Pedro Pablo Lopez-Casas3, Elisabet Llonch1, Manuel Hidalgo3, Vassilis G. Gorgoulis2,4,5 and Angel R. Nebreda1,6

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

* These authors should be considered as joint first authors

Correspondence to:

Angel R. Nebreda, email:

Keywords: colon cancer, p38 MAPK, mouse xenograft, therapy

Received: December 18, 2014 Accepted: March 03, 2015 Published: April 14, 2015

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.


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