title: Overexpression of PAK1 promotes cell survival in inflammatory bowel diseases and colitis-associated cancer.
abstract: BACKGROUND
  Chronic gut inflammation predisposes to the development of colorectal cancer and increased mortality. Use of mesalamine (5-ASA) in the treatment of ulcerative colitis modulates the risk of neoplastic progression. p21 activated kinase 1 (PAK1) mediates 5-ASA activity by orchestrating MAPK signaling, Wnt-β catenin pathway, and cell adhesion; all implicated in the colon carcinogenesis. We evaluated the role of PAK1 in IBD and in colitis-associated cancer (CAC).
  
  
  RESULTS
  PAK1 expression was scored by immunohistochemistry in human samples from IBD, CAC, and in normal mucosa. Compared with controls, a higher PAK1 expression was detected in IBD which further increased in CAC. The consequence of PAK1 overexpression was investigated using normal diploid colon epithelial cells (HCEC-1CT), which showed higher proliferation and decreased apoptosis on overexpression of PAK1. Analysis of IBD and CAC samples showed activation of AKT (p-AKT). However, mTOR pathway was activated in IBD but not in CAC. Treatment of cells with specific inhibitors (PD98059/LY294002/rapamycin) of growth signaling pathways (MEK/PI3K/mTOR) demonstrated that in HCEC-1CT, PAK1 expression is regulated by MEK, PI3K, and mTOR. In colorectal cancer cell lines, PAK1, and beta-catenin expression correlated and inhibition of PAK1 and addition of 5-ASA elicited similar molecular affects by reducing ERK and AKT activation. Moreover, 5-ASA disrupted PAK1 interaction and colocalization with β-catenin.
  
  
  CONCLUSIONS
  Our data indicate that (1) PAK1 is upregulated in IBD and CAC (2) PAK1 overexpression is associated with activation of PI3K-AKT/mTOR prosurvival pathways in IBD.
authors.affiliation: Christian Doppler Laboratory for Molecular Cancer Chemoprevention Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Khare
authors.forename: Kyle
authors.initials: K
authors.lastname: Dammann
authors.forename: Mario
authors.initials: M
authors.lastname: Asboth
authors.forename: Anita
authors.initials: A
authors.lastname: Krnjic
authors.forename: Manuela
authors.initials: M
authors.lastname: Jambrich
authors.forename: Christoph
authors.initials: C
authors.lastname: Gasche
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008856:Microscopy, Fluorescence; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C515903:PAK1 protein, human; D054462:p21-Activated Kinases