Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1

Khare, Vineeta; Lyakhovich, Alex; Dammann, Kyle; Lang, Michaela; Borgmann, Melanie; Tichý, Boris; Pospı́šilová, Šárka; Luciani, Gloria; Campregher, Christoph; Evstatiev, Rayko; Pflueger, Maren; Hundsberger, Harald; Gasché, Christoph

doi:10.1016/j.bcp.2012.10.026

Cited by 43 publications

(65 citation statements)

References 37 publications

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“…β-Catenin is an effector of Wnt, and plays a role in cell-to-cell contacts as a complex with E-cadherin at AJ 75. Inhibition of PAK1 increased the membranous localisation of both β-catenin and E-cadherin,76 thereby increasing the formation of AJ and reducing intestinal permeability. This further underlines the role of PAK1 in intestinal integrity and mucosal barrier function.…”

Section: Pak Physiology: Kinase Versus Scaffolding Functionsmentioning

confidence: 98%

Tracing PAKs from GI inflammation to cancer

Dammann

Khare

Gasché

2014

Gut

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Section: Pak Physiology: Kinase Versus Scaffolding Functionsmentioning

confidence: 98%

Tracing PAKs from GI inflammation to cancer

Dammann

Khare

Gasché

2014

Gut

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“…We previously demonstrated that PAK1 is overexpressed in tumors of APC min mice and that 5-ASA reduced both PAK1 overexpression and small bowel tumor multiplicity in these mice (10). However, it was unclear whether inhibition of PAK1 by 5-ASA was required to carry out the effect of 5-ASA on reducing tumorigenesis.…”

Section: Resultsmentioning

confidence: 99%

“…5-ASA not only induces S-phase arrest and blocks cell proliferation (6) but also reduces the activation of AKT-b-catenin (7) and NF-kB signaling (8). In addition, we recently reported that p21-activated kinase 1 (PAK1) is a 5-ASA target, and its inhibition by 5-ASA improved intestinal barrier function by increasing membranous E-cadherin and b-catenin (9,10).…”

Section: Introductionmentioning

confidence: 99%

PAK1 Promotes Intestinal Tumor Initiation

Dammann

Khare

Harpain

et al. 2015

Cancer Prevention Research

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p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC min or APC min /PAK1 À/À mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six-to 8-week-old PAK1 À/À and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC min mice. IHC revealed that PAK1 deletion reduced p-AKT, b-catenin, and c-Myc expression in APC min adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked b-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.

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“…In addition to these effects, other molecular pathways may also be involved. For instance, inhibition of PAK1 (p21-activated kinase-1), a novel pathway in carcinogenesis of colonic polyps was proposed (20). Modulation of nuclear factor kappa B (NFκB) and polyamine catabolism are also considered as possible mechanisms of antitumor activity (18,21).…”

Section: Aspirin Mechanism Of Action In Cancer Preventionmentioning

confidence: 99%

Aspirin for the Primary Prophylaxis of Colorectal Cancer

Lankarani

2013

Ann Colorectal Res

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Context: Increasing epidemic of colorectal cancer worldwide and the expenses of the current screening and treatment of this potentially fatal condition have raised the interest of in finding a primary prophylactic measure. Aspirin has been administrated for more than 40 years to achieve this. Evidence Acquisitions: In this manuscript, we reviewed the best available evidence on the prophylatic use of aspirin for colorectal cancer prevention. Results: The analysis and large cohort studies revealed that although using ASA would probably decrease the risk of colon cancer, this would not occur before 5-8 years after treatment. ASA usage would increase the risk of major gastrointestinal bleeding. Conclusions: Aspirin has been proposed as a chemopreventive agent in colorectal cancer (CRC) for many years, but there are still debates on the proper candidates, treatment time and cost benefit analysis of this potentially harmful drug. This brief review would try to answer these questions using the currently available evidence. Keywords: Aspirin; Colorectal Cancer; Primary PreventionImplication for health policy/practice/research/medical education: There is insufficient data to recommend aspirin for primary prophylaxis of colorectal cancer in general population. Aspirin for this purpose could be used in high-risk groups including those with a strong family history of colon cancer, especially in members of families with Lynch syndrome.

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Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1

Abstract: Graphical abstract(a) PAK1 orchestrates mesalamine activity, (b) mesalamine inhibits PAK1; increases membranous E-cadherin and β-catenin; modulates cell adhesion

Cited by 43 publications

References 37 publications

Tracing PAKs from GI inflammation to cancer

Tracing PAKs from GI inflammation to cancer

PAK1 Promotes Intestinal Tumor Initiation

Aspirin for the Primary Prophylaxis of Colorectal Cancer

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