4-cholesten-3-one suppresses lung adenocarcinoma metastasis by regulating translocation of HMGB1, HIF1 alpha and Caveolin-1
作者
Ma, JB;Fu, GB;Wu, J;Han, SX;Zhang, LS;Yang, M;Yu, Y;Zhang, MY;Lin, YL;Wang, YB
作者单位
[Ma, Jinben; Wu, Jing; Zhang, Mengyuan] Shandong Univ, Shandong Prov Hosp, Dept Anesthesiol, Jinan 250021, Peoples R China.;-;[Fu, Guobin] Shandong Univ, Shandong Prov Hosp, Dept Oncol, Jinan 250021, Peoples R China.;-;[Han, Shaoxian] Shandong Chest Hosp, Dept Surg, Jinan 250021, Peoples R China.;-;[Zhang, Lishan] Shandong Univ, Shandong Prov Hosp, Dept Hand & Foot Surg, Jinan 250021, Peoples R China.;-;[Yang, Ming; Yu, Yong] Shandong Univ, Shandong Prov Hosp, Dept Ultrasound, Jinan 250021, Peoples R China.;-;[Lin, Yanliang] Shandong Univ, Shandong Prov Hosp, Dept Ctr Lab, Jingwuweiqi Rd 324, Jinan 250021, Peoples R China.;-;[Wang, Yibing] Shandong Univ, Shandong Prov Hosp, Dept Burn & Plast Surg, Jinan 250021, Peoples R China.
摘要
Metastasis is a great challenge in lung adenocarcinoma (ADC) therapy. Cholesterol has been implicated in ADC metastasis. 4-cholesten-3-one, as cholesterolmetabolite and analog, can substitutemembrane cholesterol and increase membrane fluidity. In this study, we explored the possibility that 4-cholesten-3-one inhibited ADC metastasis. Low-dose 4-cholesten-3-one significantly restrained ADC cells migration and invasion with little effects on cells viabilities. Further investigation showed that 4-cholesten-3-one promoted ROS generation, which transiently activated AMPK alpha 1, increased HIF1 alpha expression, reduced Bcl-2 expression and caused autophagy. AMPKa1 knockdown partly suppressed 4-cholesten-3-one-induced autophagy but, neither prevented 4-cholesten-3-one-induced upregulation of HIF1 alpha or downregulation of Bcl-2. 4-cholesten-3-one-induced autophagy facilitated the release of HMGB1 from nuclei to cytoplasm, blocking nuclear translocation of HIF1 alpha and activation of MMP2 and MMP9. Also, 4-cholesten-3-one induced time-dependent phosphorylation of caveolin-1, Akt and NF-kappa B. With increasing treatment time, 4-cholesten-3-one accelerated caveolin-1 internalization, but reduced the phosphorylation of Akt and NF-kappa B, and inhibited the expression of snail and twist. These data suggested that 4-cholesten-3-one could be a potential candidate for anti-metastasis of lung adenocarcinoma.
关键词
METHYL-BETA-CYCLODEXTRIN; LIPID RAFTS; CHOLESTEROL DEPLETION; CANCER METASTASIS; DOWN-REGULATION; TUMOR-GROWTH; APOPTOSIS; CELL; OSTEOSARCOMA; ACTIVATION
基本信息
