Oncotarget

Research Papers:

Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells

Fei Zhao, Weiwei Huang, Zhe Zhang, Lin Mao, Yangyang Han, Jun Yan and Ming Lei _

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Oncotarget. 2016; 7:5366-5382. https://doi.org/10.18632/oncotarget.6783

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Abstract

Fei Zhao1,*, Weiwei Huang1,*, Zhe Zhang1, Lin Mao1,3, Yangyang Han1,3, Jun Yan3, Ming Lei1,2

1College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China

2Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, People's Republic of China

3State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China

*These authors contributed equally to this work

Correspondence to:

Ming Lei, e-mail: leiming@ibp.ac.cn

Keywords: triptolide, CaMKKβ, AMPK, autophagy, apoptosis

Received: July 13, 2015     Accepted: December 05, 2015     Published: December 29, 2015

ABSTRACT

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 CaMKKβ-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 CaMKKβ-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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