title: PAK1 promotes intestinal tumor initiation.
abstract: 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(-/-) mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six- to 8-week-old PAK1(-/-) 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, β-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 β-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.
authors: Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.
authors: Kyle
authors: K
authors: Dammann
authors: Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.
authors: Vineeta
authors: V
authors: Khare
authors: Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.
authors: Felix
authors: F
authors: Harpain
authors: Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.
authors: Michaela
authors: M
authors: Lang
authors: Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.
authors: Azra
authors: A
authors: Kurtovic
authors: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors: Ildiko
authors: I
authors: Mesteri
authors: Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.
authors: Rayko
authors: R
authors: Evstatiev
authors: Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria. christoph.gasche@meduniwien.ac.at.
authors: Christoph
authors: C
authors: Gasche
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000737:chemistry; D063646:Carcinogenesis; D003113:Colonoscopy; D003911:Dextrans / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006579:Heterozygote; D007150:Immunohistochemistry; D007249:Inflammation; D007414:Intestinal Neoplasms / Q000378:metabolism*; D008297:Male; D019804:Mesalamine / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D003911:Dextrans; D051176:beta Catenin; D019804:Mesalamine; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D001397:Azoxymethane