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Menges CW , Sementino E , Talarchek J , Xu JF , Chernoff J , Peterson JR , Testa JR
Group I p21-Activated Kinases (PAKs) Promote Tumor Cell Proliferation and Survival through the AKT1 and Raf-MAPK Pathways
Molecular Cancer Research. 2012 Sep;10(9) :1178-1188
PMID: WOS:000310648300005    PMCID: PMC3447107   
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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. Mol Cancer Res; 10(9); 1178-88. (C) 2012 AACR.
Notes
Menges, Craig W. Sementino, Eleonora Talarchek, Jacqueline Xu, Jinfei Chernoff, Jonathan Peterson, Jeffrey R. Testa, Joseph R. NIH [CA-114047, CA-148805, GM083025, CA-06927]; Children's Tumor Foundation [2011-15-012] This study was supported by NIH awards CA-114047 (J.R. Testa), CA-148805 (J. Chernoff, J. R. Testa), GM083025 (J. R. Peterson), and CA-06927 (Fox Chase Cancer Center), an appropriation from the Commonwealth of Pennsylvania, an award from the Children's Tumor Foundation (2011-15-012; J. Chernoff), and by a gift from the Local #14 Mesothelioma Fund of the International Association of Heat and Frost Insulators & Allied Workers in memory of Hank Vaughan and Alice Haas (J. R. T.). 42 Amer assoc cancer research Philadelphia 031ni