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.
Keywords: Invasion; Non–small cell lung cancer; P21-activated kinase 1; Proliferation.