PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation

Tumour Biol. 2012 Aug;33(4):985-94. doi: 10.1007/s13277-012-0327-1. Epub 2012 Jan 18.


P21-activated protein kinase1 (PAK1), a main downstream effector of small Rho GTPases, Rac1, and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Despite its importance, the molecular mechanisms of PAK1 that contributed to colorectal carcinogenesis remain unclear. Our immunohistochemistry showed that PAK1 expression was increased with colorectal cancer (CRC) progression through the adenoma to carcinoma sequence. Furthermore, our results suggested a relationship between PAK1 nuclear localization and the Dukes staging. In the present study, we showed that PAK1 knockdown decreased proliferation and delayed the G1/S cell-cycle transition, and increased apoptosis in vivo and in vitro. In addition, PAK1 knock-down downregulated c-Jun amino terminal kinases (JNK) activity and the levels of cyclinD1, CDK4/6. Inhibition of the JNK activity by chemical inhibitor (SP600125) significantly reduced the effects of PAK1 on CRC proliferation via accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In conclusion, our results demonstrate that knockdown of PAK1 could enhance the chemosensitivity of CRCs to 5-fluorouracil through G1 arrest. The mechanism by which PAK1 induced cancer growth might involve activation of JNK as well as downregulation of PTEN. Targeting PAK1 may represent a novel treatment strategy for developing novel chemotherapeutic agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracenes / pharmacology
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / metabolism
  • Fluorouracil / pharmacology
  • G1 Phase / drug effects
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Nude
  • PTEN Phosphohydrolase / metabolism
  • RNA Interference
  • Xenograft Model Antitumor Assays / methods
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*


  • Anthracenes
  • Antimetabolites, Antineoplastic
  • Cyclin D1
  • pyrazolanthrone
  • PAK1 protein, human
  • p21-Activated Kinases
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • JNK Mitogen-Activated Protein Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Fluorouracil