低浓度右美托咪定经ERK1/2依赖方式促进TRIO、PKN2和CKAP5介导的骨肉瘤细胞增殖和侵袭OA

Objective To investigate the effect of Dexmedetomidine(Dex)on osteosarcoma(OS)cells and its underlying mechanism.Methods The optimal exposure concentrations of Dex,α2-adrenergic receptor(α2-AR)antagonist,PKA inhibitor,and ERK1/2 inhibitor were determined by MTT assay.Genes positively correlated with ERK1/2 expression in OS samples and potentially mediating its tumor-promoting effect were extracted from the GEPIA database,and their expression levels in OS cells were verified by qRT-PCR and Western blot.After silencing candidate genes with siRNA,MTT assay,flow cytometry,Transwell assay,and colony formation assay were performed to evaluate the role of ERK1/2 pathway genes in the processes by which Dex affects OS cell proliferation,apoptosis,invasion,and colony formation ability.Results 25 nM Dex was the optimal concentration for promoting OS cell viability.The ERK1/2 inhibitor(Ravoxertinib)significantly antagonized the enhancement of OS cell viability induced by low-concentration Dex,whereas inhibition of α2-AR or PKA exerted weaker effects.Bioinformatics analysis identified that TRIO,PKN2,CKAP5,and NEK4 were highly associated with the oncogenic function of ERK1/2 in OS.Western blot demonstrated that Ravoxertinib blocked the upregulation of TRIO,PKN2,CKAP5,and NEK4 induced by Dex.Silencing TRIO,PKN2,or CKAP5 effectively suppressed Dex-induced increases in OS cell viability,invasion capacity,and colony formation,while attenuating the inhibitory effect of Dex on cell apoptosis.Conclusion Low-concentration Dex upregulates the expression of TRIO,PKN2,and CKAP5 in an ERK1/2-dependent manner,thereby promoting the malignant biological potential of OS cells.