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Title: Tetrandrine, an activator of autophagy, induces autophagic cell death via PKC-alpha inhibition and mTOR-dependent mechanisms
Authors: Wong, VKW
Zeng, W
Chen, J
Yao, XJ
Leung, ELH
Wang, QQ
Chiu, P
Ko, BCB 
Law, BYK
Issue Date: 8-Jun-2017
Source: Frontiers in pharmacology, 8 June 2017, v. 8, 351, p. 1-13
Abstract: Emerging evidence suggests the therapeutic role of autophagic modulators in cancer therapy. This study aims to identify novel traditional Chinese medicinal herbs as potential anti-tumor agents through autophagic induction, which finally lead to autophagy mediated-cell death in apoptosis-resistant cancer cells. Using bioactivity-guided purification, we identified tetrandrine (Tet) from herbal plant, Radix stephaniae tetrandrae, as an inducer of autophagy. Across a number of cancer cell lines, we found that breast cancer cells treated with tetrandrine show an increase autophagic flux and formation of autophagosomes. In addition, tetrandrine induces cell death in a panel of apoptosis-resistant cell lines that are deficient for caspase 3, caspase 7, caspase 3 and 7, or Bax-Bak respectively. We also showed that tetrandrine-induced cell death is independent of necrotic cell death. Mechanistically, tetrandrine induces autophagy that depends on mTOR inactivation. Furthermore, tetrandrine induces autophagy in a calcium/calmodulin-dependent protein kinase kinase-beta (CaMKK-beta), 5' AMP-activated protein kinase (AMPK) independent manner. Finally, by kinase profiling against 300 WT kinases and computational molecular docking analysis, we showed that tetrandrine is a novel PKC-alpha inhibitor, which lead to autophagic induction through PKC-alpha inactivation. This study provides detailed insights into the novel cytotoxic mechanism of an anti-tumor compound originated from the herbal plant, which may be useful in promoting autophagy mediated-cell death in cancer cell that is resistant to apoptosis.
Keywords: Autophagy
Tetrandrine
Apoptosis-resistant
MTOR
PKC-alpha
Publisher: Frontiers Research Foundation
Journal: Frontiers in pharmacology 
ISSN: 1663-9812
EISSN: 1663-9812
DOI: 10.3389/fphar.2017.00351
Rights: Copyright © 2017 Wong, Zeng, Chen, Yao, Leung, Wang, Chiu, Ko and Law. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The following publication Wong VKW, Zeng W, Chen J, Yao XJ, Leung ELH, Wang QQ, Chiu P, Ko BCB and Law BYK (2017) Tetrandrine, an Activator of Autophagy, Induces Autophagic Cell Death via PKC-α Inhibition and mTOR-Dependent Mechanisms. Front. Pharmacol. 8:351,1-13 is available at https://dx.doi.org/10.3389/fphar.2017.00351
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