期刊
ONCOTARGET
卷 7, 期 5, 页码 5366-5382出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6783
关键词
triptolide; CaMKK beta; AMPK; autophagy; apoptosis
资金
- National Forestry Public Welfare Industry Research Project [201204603]
- National Natural Science Foundation of China [31571194, 31540002, 81172009, 31300654]
- Research Innovation Team Project of Shaanxi [2013KCT-27]
- Fundamental Research Funds for Universities [014YB034]
Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent anti-tumor activity. Recently, triptolide was found to induce autophagy in cancer cells. However, the effects of triptolide on autophagy in human prostate cancer (PCa) cells have not yet been clearly elucidated. In this study, we demonstrated that triptolide induces autophagy in three PCa cell lines, PC-3, LNCaP and C4-2. Furthermore, we found that triptolide mediates intracellular accumulation of free calcium by stimulating the endoplasmic reticulum (ER) stress response. This activates the CaMKK beta-AMPK signaling pathway, which in turn inhibits mTOR and activates both ULK1 and Beclin 1, finally resulting in autophagy. Moreover, we found that treatment with autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhances triptolide-induced PCa cell death and growth inhibition. Using a PC-3-xenografted mouse model, we showed that blocking autophagy with CQ significantly promoted triptolide-induced tumor growth inhibition in vivo. Overall, our results show that triptolide induces protective autophagy through the CaMKK beta-AMPK pathway in PCa cells, implying that a combination of triptolide with autophagy inhibitors may potentially be an effective therapeutic strategy for PCa.
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