Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/76301
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
Keywords: Autophagy
Tetrandrine
Apoptosis-resistant
MTOR
PKC-alpha
Issue Date: 2017
Publisher: Frontiers Research Foundation
Source: Frontiers in pharmacology, 2017, v. 8, 351 How to cite?
Journal: Frontiers in pharmacology 
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.
URI: http://hdl.handle.net/10397/76301
ISSN: 1663-9812
EISSN: 1663-9812
DOI: 10.3389/fphar.2017.00351
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