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Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2349-60. doi: 10.1016/j.bbamcr.2015.05.031. Epub 2015 May 31.

PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation.

Author information

1
Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria.
2
Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Hans Popper Laboratory for Molecular Hepatology, Vienna, Austria.
3
Department of Gastroenterology, University of Liverpool, Liverpool, United Kingdom.
4
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
5
Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria. Electronic address: christoph.gasche@meduniwien.ac.at.

Abstract

P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNFα injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFα. NF-κB and PPARγ were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFNγ, IL-1β, and TNFα. In vivo, mice administered with TNFα showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-κB activation. p65 nuclear translocation downstream of TNFα was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-κB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARγ and mesalamine recovered PPARγ through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-κB, which was recovered using BADGE, a PPARγ antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-κB activity via suppression of PPARγ in intestinal epithelial cells.

KEYWORDS:

Colitis-associated cancer; Inflammation; NF-κB; PAK1; PPARγ; Ulcerative colitis

PMID:
26036343
PMCID:
PMC4576212
DOI:
10.1016/j.bbamcr.2015.05.031
[Indexed for MEDLINE]
Free PMC Article

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