Group I p21-Activated Kinases (PAKs) Promote Tumor Cell Proliferation and Survival through the AKT1 and Raf-MAPK Pathways

Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. .
Molecular Cancer Research (Impact Factor: 4.38). 07/2012; 10(9):1178-88. DOI: 10.1158/1541-7786.MCR-12-0082
Source: PubMed


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. ©2012 AACR.

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    • "However, the observed activation of multiple RTKs in mesothelioma suggests that transforming activity is dependent on coordinated activity of multiple tyrosine kinases (Kawaguchi et al, 2009; Menges et al, 2010; Perrone et al, 2010; Brevet et al, 2011; Ou et al, 2011b), and simultaneous inhibition of multiple kinases by cocktails of small-molecule kinase inhibitors or single-agent HSP90 inhibitors elicits compelling pro-apoptotic and anti-proliferative responses in mesothelioma preclinical models (Okamoto et al, 2008; Kawaguchi et al, 2009; Ou et al, 2011b). In addition to the evidence for PI3K/AKT and RAF/MEK/MAPK activation in mesothelioma initiation, there is likewise substantial evidence that these key signalling pathways are crucial in maintaining the transformed state, and in mesothelioma metastasis (Altomare et al, 2005; Cole et al, 2006; Patel et al, 2007; Jacobson et al, 2009; Suzuki et al, 2009; Shukla et al, 2011; Carbone and Yang, 2012; Cedres et al, 2012; Fischer et al, 2012; Menges et al, 2012; Miyoshi et al, 2012; Pinton et al, 2012). "
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