Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways

Mol Cancer Res. 2012 Sep;10(9):1178-88. doi: 10.1158/1541-7786.MCR-12-0082. Epub 2012 Jul 12.

Abstract

Group I p21-activated kinases (PAK) are important effectors of the small GTPases Rac and Cdc42, which regulate cell motility/migration, survival, proliferation, and gene transcription. Hyperactivation of these kinases have been reported in many tumor types, making PAKs attractive targets for therapeutic intervention. PAKs are activated by growth factor-mediated signaling and are negatively regulated by the tumor suppressor neurofibromatosis type 2 (NF2)/Merlin. Thus, tumors characterized by NF2 inactivation would be expected to show hyperactivated PAK signaling. On the basis of this rationale, we evaluated the status of PAK signaling in malignant mesothelioma, an aggressive neoplasm that is resistant to current therapies and shows frequent inactivation of NF2. We show that group I PAKs are activated in most mesotheliomas and mesothelioma cell lines and that genetic or pharmacologic inhibition of PAKs is sufficient to inhibit mesothelioma cell proliferation and survival. We also identify downstream effectors and signaling pathways that may contribute mechanistically to PAK-related tumorigenesis. Specifically, we show that inhibition of PAK results in attenuation of AKT and Raf-MAPK signaling and decreased tumor cell viability. Collectively, these data suggest that pharmacologic inhibition of group I PAKs may have therapeutic efficacy in tumors characterized by PAK activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disulfides / pharmacology*
  • Electrophoresis, Gel, Two-Dimensional
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Knockdown Techniques
  • Humans
  • Mesothelioma / drug therapy
  • Mesothelioma / genetics*
  • Mesothelioma / metabolism
  • Mice
  • Naphthols / pharmacology*
  • Neurofibromin 2 / antagonists & inhibitors
  • Neurofibromin 2 / genetics*
  • Neurofibromin 2 / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • p21-Activated Kinases / antagonists & inhibitors
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism

Substances

  • Disulfides
  • IPA-3 compound
  • Naphthols
  • Neurofibromin 2
  • PAK1 protein, human
  • PAK2 protein, human
  • Proto-Oncogene Proteins c-akt
  • p21-Activated Kinases