Blockage of PAK1 alleviates the proliferation and invasion of NSCLC cells via inhibiting ERK and AKT signaling activity

Purpose P21-activated kinase 1 (PAK1), a serine/threonine protein kinase which functions downstream of RAC and CDC42 GTPase, is activated by a variety of stimuli, including RAS and other growth signaling factors. The extracellular signal kinase (ERK) and protein kinase B (AKT) signal pathways have been implicated in the pathogenesis of cancers. Whether PAK1 is sensitive to KRAS mutation signals and plays a role through ERK and AKT signaling pathways in NSCLC needs to be studied. Methods The expression of PAK1, ERK and AKT was detected in both lung cancer cell lines and clinical samples. PAK1 RNA interference and specific inhibitor of PAK1(IPA-3) were applied to lung cancer cell lines and mouse xenograft tumors. Cell growth was measured by MTT and colony formation assays. Cell migration and invasion were detected by wound healing and transwell assays. RAS mutation was detected by Taqman probe method. Correlation between KRAS, PAK1, ERK and AKT activities was analyzed in lung cancer patients. Results PAK1 was highly expressed not only in RAS mutant but also in RAS wild-type lung cancer cells. Using specific inhibitor of PAK1, IPA-3 and PAK1 RNA interference, cell proliferation, migration and invasion of lung cancer cells were reduced significantly, accompanied by decreased activities of ERK and AKT. Dual inhibition of ERK and AKT suppressed these cellular processes to levels comparable to those achieved by reduction in PAK1 expression. In NSCLC patients, PAK1 was not correlated with KRAS mutation but was significantly positively correlated with pERK and pAKT. Conclusion PAK1 played roles in NSCLC proliferation and invasion via ERK and AKT signaling and suggested a therapeutic target for NSCLC.

Automated summary

PAK1, downstream of RAC and CDC42 GTPase, is activated by various stimuli including RAS and growth signaling factors. Study shows PAK1 is not only highly expressed in RAS mutant lung cancer cells but also in RAS wild-type cells. Inhibition of PAK1 significantly reduces cell proliferation, migration and invasion in lung cancer cells through ERK and AKT signaling pathways. In NSCLC patients, PAK1 is positively correlated with pERK and pAKT but not with KRAS mutation.