期刊
CELL DEATH & DISEASE
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2016.281
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资金
- National Natural Science Foundation of China [81201778, 81201471, 81171818, 81572272]
- Promotive research fund for excellent young and middle-aged scientists of Shandong Province [BS2011SW036, BS2013YY065]
- Foundation for Outstanding Young Scientist in Shandong Province [BS2013YY058]
- Science and Technology Development Plan Project of Shandong Province [2014GSF118157]
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.
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