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

Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, Gorgoulis VG, Nebreda AR - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), 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.

No MeSH data available.


Related in: MedlinePlus

Effect of the p38 MAPK inhibitor in cytokine production by PDXsRelative expression levels of the indicated mRNAs were determined by qRT-PCR and were normalized to the expression levels of initial tumors, which were given the value of 1. Samples of PDXs were collected as in Figure 3. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
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Figure 5: Effect of the p38 MAPK inhibitor in cytokine production by PDXsRelative expression levels of the indicated mRNAs were determined by qRT-PCR and were normalized to the expression levels of initial tumors, which were given the value of 1. Samples of PDXs were collected as in Figure 3. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.

Mentions: There is good evidence that IL-6 family cytokines (IL-11 and IL-6) and STAT3 signaling are important for the survival and proliferation of colon tumor cells in mouse models [28-32]. Moreover, the chemokine receptor CXCR-2 and its ligands CXCL-1 and CXCL-2 have been proposed to facilitate the growth of spontaneous and inflammation-associated colon tumors [33]. Genetic downregulation of p38α in AOM/DSS-induced mouse colon tumors reduces tumor growth, which correlates with reduced levels of IL-6, IL-11, CXCL-1 and CXCL-2 [20]. Since p38 MAPK inhibition reduced tumor growth in the three PDXs models from CRC, we investigated whether similar mechanisms were involved as in mouse colon tumors. Gene expression analysis showed that in CCR-010 tumors, IL-6, CXCL-1 and CXCL-2 mRNAs were all downregulated at both early and late time points upon p38 MAPK inhibition compared to vehicle treatment (Figure 5). Expression of IL-6 and CXCL-1 mRNAs was also reduced at both time points analyzed in CCR-024 tumors treated with PH797804, while CXCL-2 mRNA expression was only reduced at the late time point (Figure 5). In CCR-038 tumors, the expression of IL-6, CXCL-1 and CXCL-2 mRNAs was significantly downregulated only at the early time point upon PH797804 treatment (Figure 5). In contrast, the expression of IL-11 mRNA was only affected by p38 MAPK inhibition at the late time point in CCR-038 tumors but not in the other two PDXs (Suppl. Figure S3).


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

Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, Gorgoulis VG, Nebreda AR - Oncotarget (2015)

Effect of the p38 MAPK inhibitor in cytokine production by PDXsRelative expression levels of the indicated mRNAs were determined by qRT-PCR and were normalized to the expression levels of initial tumors, which were given the value of 1. Samples of PDXs were collected as in Figure 3. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496165&req=5

Figure 5: Effect of the p38 MAPK inhibitor in cytokine production by PDXsRelative expression levels of the indicated mRNAs were determined by qRT-PCR and were normalized to the expression levels of initial tumors, which were given the value of 1. Samples of PDXs were collected as in Figure 3. Data represent means ± SEM (n ≥ 4). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
Mentions: There is good evidence that IL-6 family cytokines (IL-11 and IL-6) and STAT3 signaling are important for the survival and proliferation of colon tumor cells in mouse models [28-32]. Moreover, the chemokine receptor CXCR-2 and its ligands CXCL-1 and CXCL-2 have been proposed to facilitate the growth of spontaneous and inflammation-associated colon tumors [33]. Genetic downregulation of p38α in AOM/DSS-induced mouse colon tumors reduces tumor growth, which correlates with reduced levels of IL-6, IL-11, CXCL-1 and CXCL-2 [20]. Since p38 MAPK inhibition reduced tumor growth in the three PDXs models from CRC, we investigated whether similar mechanisms were involved as in mouse colon tumors. Gene expression analysis showed that in CCR-010 tumors, IL-6, CXCL-1 and CXCL-2 mRNAs were all downregulated at both early and late time points upon p38 MAPK inhibition compared to vehicle treatment (Figure 5). Expression of IL-6 and CXCL-1 mRNAs was also reduced at both time points analyzed in CCR-024 tumors treated with PH797804, while CXCL-2 mRNA expression was only reduced at the late time point (Figure 5). In CCR-038 tumors, the expression of IL-6, CXCL-1 and CXCL-2 mRNAs was significantly downregulated only at the early time point upon PH797804 treatment (Figure 5). In contrast, the expression of IL-11 mRNA was only affected by p38 MAPK inhibition at the late time point in CCR-038 tumors but not in the other two PDXs (Suppl. Figure S3).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), 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.

No MeSH data available.


Related in: MedlinePlus