TY - JOUR
T1 - Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors
AU - Gupta, Jalaj
AU - Igea, Ana
AU - Papaioannou, Marilena
AU - Lopez-Casas, Pedro Pablo
AU - Llonch, Elisabet
AU - Hidalgo, Manuel
AU - Gorgoulis, Vassilis G.
AU - Nebreda, Angel R.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Colon cancer
KW - Mouse xenograft
KW - Therapy
KW - p38 MAPK
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UR - http://www.scopus.com/inward/citedby.url?scp=84928753284&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3816
DO - 10.18632/oncotarget.3816
M3 - Article
AN - SCOPUS:84928753284
VL - 6
SP - 8539
EP - 8551
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 11
ER -