Abstract
BackgroundKey effector(s) of mutated KRAS in lung cancer progression and metastasis are unknown. Here we investigated the role of PAK1/Crk axis in transduction of the oncogenic KRAS signal in non-small cell lung cancer (NSCLC).MethodsWe used NSCLC clinical specimens to examine the correlation among KRAS mutations (codon 12, 13 and 61); PAK1/Crk axis activation [p-PAK1(Thr423), p-Crk(Ser41)]; and adhesion molecules expression by immunohistochemistry. For assessing the role of proto-oncogene c-Crk as a KRAS effector, we inhibited KRAS in NSCLC cells by a combination of farnesyltransferase inhibitor (FTI) and geranylgeranyltransferase inhibitor (GGTI) and measured p-Crk-II(Ser41) by western blotting. Finally, we disrupted the signaling network downstream of KRAS by blocking KRAS/PAK1/Crk axis with PAK1 inhibitors (i.e., IPA-3, FRAX597 or FRAX1036) along with partial inhibition of all other KRAS effectors by prenylation inhibitors (FTI + GGTI) and examined the motility, morphology and proliferation of the NSCLC cells.ResultsImmunohistochemical analysis demonstrated an inverse correlation between PAK1/Crk phosphorylation and E-cadherin/p120-catenin expression. Furthermore, KRAS mutant tumors expressed higher p-PAK1(Thr423) compared to KRAS wild type. KRAS prenylation inhibition by (FTI + GGTI) completely dephosphorylated proto-oncogene c-Crk on Serine 41 while Crk phosphorylation did not change by individual prenylation inhibitors or diluent. Combination of PAK1 inhibition and partial inhibition of all other KRAS effectors by (FTI + GGTI) dramatically altered morphology, motility and proliferation of H157 and A549 cells.ConclusionsOur data provide evidence that proto-oncogene c-Crk is operative downstream of KRAS in NSCLC. Previously we demonstrated that Crk receives oncogenic signals from PAK1. These data in conjunction with the work of others that have specified the role of PAK1 in transduction of KRAS signal bring forward the importance of KRAS/PAK1/Crk axis as a prominent pathway in the oncogenesis of KRAS mutant lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1360-4) contains supplementary material, which is available to authorized users.
Highlights
Key effector(s) of mutated KRAS in lung cancer progression and metastasis are unknown
Phosphorylation of p21 activated kinase 1 (PAK1)/Crk is inversely correlated with E-cadherin/p120-catenin expression in clinical non-small cell lung cancer (NSCLC) specimens Our previous work showed that PAK1 phosphorylates adaptor protein Crk on serine 41 which in turn increases motility and invasiveness of lung cancer cells
We sought to investigate whether PAK1, Crk, p120catenin and E-cadherin establish a correlation with each other in clinical lung cancer specimens
Summary
Key effector(s) of mutated KRAS in lung cancer progression and metastasis are unknown. We investigated the role of PAK1/Crk axis in transduction of the oncogenic KRAS signal in non-small cell lung cancer (NSCLC). KRAS mutant lung cancer comprises 25-30% of lung adenocarcinomas and no effective treatment is currently available for this sub-type of non-small cell lung cancer (NSCLC). One strategy to interrupt the oncogenic KRAS signal is to block the key downstream effector(s) of this oncogene. PAK1 kinase was shown to play a role in transduction of the KRAS signal [1,2,3,4]. Exposure of cells that harbor KRAS or NRAS mutations to PAK1 inhibitor (IPA-3) resulted. Mortazavi et al BMC Cancer (2015) 15:381
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