The Mechanism Of SRPK1 Enhanced GSK3? Autophosphorylation And Inhibited ?-catenin Degradation To Promote NSCLC Gefitinib Resistant

80% of lung cancer types are non-small cell lung cancer(NSCLC),and the fatality rate is the highest among all cancers.NSCLC patients are advanced stage of cancer while diagnosis,and the effect of radiotherapy and chemotherapy is not good.The median survival time of metastatic NSCLC is only 8-10 months.At present,molecular targeted therapy,represented by tyrosine kinase inhibitor(TKI),has become the main treatment for NSCLC patients,which can effectively prolong the survival of patients with specific gene mutations.Gefitinib is the first generation of tyrosine kinase inhibitors(TKI)for the treatment of NSCLC patients with EGFR-activated mutations.Most of NSCLC patients with EGFR mutation are sensitive to TKI,but after 8-9 months of treatment,about 80-90% of patients will become resistant to TKI.At present,the mechanism and effective treatment for Gefitinib-resistant NSCLC patients is not clear.Serine-arginine protein kinase 1(SRPK1)is a kinase of SRSF1/2,which contains the domain of PKC superfamily kinase.Our previous studies showed that SRPK1 can enhance the cancer stem cells like phenotype in NSCLC which is closely related to the drug resistance,suggesting that SRPK1 may play a key role in the resistance of NSCLC to Gefitinib.This article focuses on the mechanism of SRPK1 involved in NSCLC Gefitinib resistance.The main research contents are as follows:1.Detection of SRPK1 expression in Gefitinib-sensitive and Gefitinib-resistant cells.The result showed that SRPK1 was highly expressed in NSCLC Gefitinib-resistant cells,and low expressed in NSCLC Gefitinib-sensitive cells.GSEA analysis confirmed that SRPK1 was significantly associated with Gefitinib resistance.2.In vitro and in vivo,the sensitivity of Gefitinib was detected in the constructed SRPK1-overexpressing or-knock down cells.It was found that SRPK1-overexpressing promoted the Gefitinib resistance through reducing the expression of apoptosis proteins,while down-regulation of SRPK1-expressing cells enhanced the sensitivity of Gefitinib by up-regulating the expression of apoptosis proteins.3.The study of signal pathway activation found that SRPK1 directly interacts with GSK3?,enhances the autophosphorylation of GSK3? Ser9,inhibits the degradation of ?-catenin and promotes the translocation of ?-catenin into the nucleus,thus activating the Wnt/?-catenin signaling pathway and enhancing the expression of downstream anti-apoptotic genes.Therefore,SRPK1 promotes NSCLC resistance to Gefitinib by activating the Wnt/?-catenin signaling pathway.In conclusion,this study found that SRPK1 participates in the resistance of NSCLC to Gefitinib and confirms the important role of SRPK1 in Wnt/?-catenin signaling pathway,which provides a scientific basis for SRPK1 to become a new therapeutic target for Gefitinib-resistant NSCLC patients.