PAK3通过激活ERK1活性介导非小细胞肺癌对吉非替尼耐药

PAK3 mediates Gefitinib resistance to non-small cell lung cancer by activating ERK1 activity

目的:探讨p21激活激酶3(PAK3)在介导非小细胞肺癌(non-small cell lung cancer,NSCLC)对吉非替尼耐药过程中的作用和分子机制。方法:我们通过免疫组化方法检测了肺腺癌患者在出现吉非替尼耐药前后PAK3的表达模式,并通过Western Blot检测了PAK3在肺癌细胞系HCC827和PC9吉非替尼耐药前后的表达模式。应用PAK3-siRNA下调肺癌细胞系中PAK3的表达后,通过Western Blot和细胞功能学实验,检测肺癌细胞系的增殖、侵袭能力及ERK1的活性变化。抑制ERK1的活性后,转染PAK3-cDNA质粒,检测肺癌细胞系的增殖、侵袭能力及其对吉非替尼的敏感性变化。结果:PAK3在肺癌组织和细胞系对吉非替尼耐药后出现显著增强;在肺癌细胞系中,PAK3能够促进肺癌细胞增殖、侵袭能力及相关蛋白的表达,激活ERK1的活性,并减弱肺癌细胞系对吉非替尼的敏感性。抑制ERK1的活性后,PAK3的表达上调对肺癌细胞恶性表型的促进作用,及其对吉非替尼耐药的促进作用显著减弱。结论:PAK3通过激活ERK1促进肺癌细胞的增殖和侵袭能力,进而促进NSCLC对吉非替尼耐药。

Objective:To investigate the role and molecular mechanism of p21 activated kinase 3(PAK3) in the Gefitinib resistance in non-small cell lung cancer(NSCLC).Methods:Using immunohistochemical methods,we compared the expression patterns of PAK3 in lung adenocarcinoma patients before and after Gefitinib resistance.Using Western Blot,we compared PAK3 expressionin lung cancer cell lines HCC827 and PC9 before and after Gefitinib resistance.After downregulating PAK3 in lung cancer cells using PAK3-siRNA,we detected the proliferation,invasion,and ERK1 activity by Western Blot and cellular functional experiments.After inhibiting the activity of ERK1,the PAK3-cDNA plasmid was transfected to detect the proliferation,invasion,and the sensitivity to Gefitinib.Results:PAK3 expression showed significantly increased in the lung cancer tissues and cell lines after Gefitinib resistance.PAK3 promoted the cell proliferation,invasion,and the related proteins expression in lung cancer cells.PAK3 activated the activity of ERK1 and reduced the sensitivity of lung cancer cell lines to Gefitinib.After inhibiting the activity of ERK1,upregulated PAK3 expression didn' t significantly promote the cell malignant phenotype and its Gefitinib resistance.Conclusion:PAK3 promotes the proliferation and invasion ability of lung cancer cells by activating ERK1,then promotes NSCLC resistance to Gefitinib.