Overexpression of PAK1 promotes cell survival in inflammatory bowel diseases and colitis-associated cancer

Inflamm Bowel Dis. 2015 Feb;21(2):287-96. doi: 10.1097/MIB.0000000000000281.


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).

Methods and 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Case-Control Studies
  • Cell Proliferation*
  • Cells, Cultured
  • Colitis / complications
  • Colitis / metabolism
  • Colitis / pathology*
  • Colon / metabolism
  • Colon / pathology
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Humans
  • Immunoenzyme Techniques
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / metabolism
  • Inflammatory Bowel Diseases / pathology*
  • Microscopy, Fluorescence
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*


  • RNA, Messenger
  • PAK1 protein, human
  • p21-Activated Kinases