The Level Of Phosphorylated Ataxia-telangiectasia Mutated Facilitates Lung Cancer Metastasis Via F-actin Remodeling

Our previous studies showed that tumor associated pro-inflammatory cytokines such as IL-6,TNF-alpha activate the phosphorylation of ataxia-telangiectasis mutated(ATIM)and promote lung cancer metastasis.Except for EMT and MMPs activaties,F-actin remodeling is another key factor contributes to metastasis.But,until now,the exact role of F-actin remodeling in inflammation-promoted metastasis is still unclear.In the present study,F-actin dynamics were firstly demonstrated to be involved in IL-6,TNF-alpha correlated cell migration.The level of phosphorylated ATM regulated by siRNA silencing or pro-inflammatory cytokines treatment and the level of phosphorylated CRMP2 induced by ATM inhibition were determined by western blot.And the dynamics of F-actin with FITC-phalloidin staing were determined by flow cytometry and confocal fluorescence microscope.Lung cancer cells’ migration ability was measured by cell migration assay.Firstly,the treatment with IL-6 or TNF-alpha obviously increased ATM phosphorylation and F-actin dynamics in lung cancer cells;secondly,the silencing of ATM not only inhibited F-actin remodeling but also decreased the abilities of migration in lung cancer cells;importantly,the level of phosphorylated CRMP2,which is an important regulator of F-actin remodeling,was down-regulated by the inhibitor of ATM activation;interestingly,inflammation-associated ROS contributed to ATM phosphorylation regulating F-actin dynamics and metastasis.Besides,the in vivo test showed that ATM knockdown suppresses lung cancer metastasis via down-regulation of p-CRMP2.Most importantly,the relationship between ATM and CRMP2 was then determined by IHC in lung cancer tissue of 53 patients.Taken together,these findings demonstrate that inflammation promotes lung cancer metastasis by ROS associated ATM phosphorylation regulating F-actin dynamic and phosphorylated CRMP2,indicating that ATM and CRMP2 are promising potential therapeutic target molecules for inflammation-associated lung cancer metastasis.