AURKA激活JAK2/STAT3通路抑制铁死亡促进神经胶质瘤细胞替莫唑胺耐药

打开文本图片集

【中图分类号】R739.4 【文献标识码】A

【Abstract】Objective To investigate the impact Aurora kinase A （AURKA） on Temozolomide （TMZ） resistance in glioma cels and its regulatory role in ferroptosis.Methods expression prile AURKA in glioma and its correlation with prognosis were explored using the GEPIA2 database.U87MG/TMZ and LN229/TMZ drug-resistant cellines were established，and the mRNA and protein expression levels AURKA were detected byqRT-PCR and Western blot，respectively.AURKA was silenced using siRNA，and dynamic monitoring lipid peroxidation levels，intracellular iron content，and glutathione peroxidase 4（GPX4） expresion was conducted using BODIPY-C11 staining， FerroOrange iron probe，and immunluorescence，respectively. Cellviabilityand IC50 were aessdbythe CCK-8 assyand cell apoptosis was detected by TUNEL staining.Following STAT3 activator treatment， JAK2/STAT3 pathway activity was detected by Western blot，and the molecular association between AURKA and ferroptosis regulation was evaluated. Results AURKA was highly expressd in glioma tissues， which was significantly associated with poor prognosis patients. AURKA expresion was significantly upregulated in U87MG/TMZ and LN229/TMZ resistant cells compared to parental cells. After AURKA silencing， lipid peroxidation products and free iron levels increased， while GPX4 protein expression decreased in U87MG/TMZ and LN229/TMZ cels. Ferroptosis inhibitor partially reversed the decrease in cellviability and TMZ resistance induced by AURKA knockdown. AURKA silencing significantly inhibited JAK2/STAT3 pathway activation; exogenous activation STAT3 （Colivelin） partially restored cell viability and atenuated the promotion ferroptosis by AURKA knockdown. Conclusion AURKA enhances TMZ resistance in glioma cels by inhibiting ferroptosis through the activation the JAK2/STAT3 pathway.

【KeyWords】Glioma cells; AURKA; Ferroptosis; JAK2/STAT3; Temozolomide resistance

神经胶质瘤是最常见原发性脑肿瘤，约占中枢神经系统肿瘤的 50%～60% ，颅内恶性肿瘤的81%[1-2] 。（剩余14178字）