Abstract 3712: p21-activated kinase-1 in the prevention of inflammation-driven colon cancer.

Abstract

Abstract Chronic gut inflammation in inflammatory bowel diseases (IBD) predisposes to the development of colorectal cancer, causing increased mortality. Use of mesalamine in the treatment and remittance of ulcerative colitis (UC) modulates the risk of neoplastic progression. We have previously reported (Khare V, et al. Biochem Pharm 2012) that p-21 activated kinase-1 (PAK1) mediates mesalamine activity by orchestrating MAPK signaling; Wnt-β catenin pathway and cell adhesion; all implicated in the colon carcinogenesis. Since mesalamine has primarily an anti-inflammatory function, we evaluated the role of PAK1, its target, in IBD and in colitis-associated cancer (CAC). PAK1 expression was scored by immunohistochemistry in human samples from IBD, CAC and normal mucosa. Compared to normal mucosa and Crohn's disease, a higher PAK1 expression was detected in UC which further increased in CAC. PAK1 expression was also elevated in the inflamed mucosa and carcinomas in IL-10−/− mouse model of colitis. The efficacy of mesalamine in reducing inflammation and tumor incidence in these mice has been previously reported (Brown JB et al, Gastroenetrology 2010). The consequence of PAK1 overexpression was further investigated in vitro. Normal diploid colon epithelial cells (HCEC-1CT) showed higher proliferation (46 ± 3.1% increase) upon overexpression of wildtype (wt) PAK1 while dominant negative (dn) PAK1 overexpression reduced proliferation (25% ± 2.5 decrease) compared to control. Apoptosis (Annexin V staining) was reduced in HCEC-1CT overexpressing wtPAK1 (1.2% ± 0.40) compared to dnPAK1 (11.6% ± 0.3) and control (16% ± 0.83). Mesalamine treatment (20mM) was effective in counteracting the effect of PAK1 overexpression by reducing cell proliferation and inducing apoptosis. Treatment of cells with specific inhibitors (PD98059/LY294002/Rapamycin) of signaling pathways (MEK/PI3K/mTOR) demonstrated that mesalamine regulated PAK1 expression by the MEK, PI3K and mTOR signaling pathways. Our data indicate that (1) PAK1 is upregulated in UC and in CAC, (2) PAK1 may be utilized as a predictive marker for the development of CAC, and (3) PAK1 is a viable target for chemoprevention in the setting of colitis. Mesalamine counteracts PAK1 expression and its effect on cell proliferation and apoptosis. In the longterm management of UC mesalamine may protect from CAC through inhibition of PAK1. Citation Format: Vineeta Khare, Kyle Dammann, Manuela Jambrich, Andres Roig, Jerry Shay, Christoph Gasche. p21-activated kinase-1 in the prevention of inflammation-driven colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3712. doi:10.1158/1538-7445.AM2013-3712