Low-concentration Dexmedetomidine promotes the proliferation and invasion of osteosarcoma cells mediated by TRIO, PKN2 and CKAP5 via ERK1/2-dependent activation

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.