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Article: Tetrandrine, an activator of autophagy, induces autophagic cell death via PKC-α inhibition and mTOR-dependent mechanisms.

TitleTetrandrine, an activator of autophagy, induces autophagic cell death via PKC-α inhibition and mTOR-dependent mechanisms.
Authors
Issue Date2017
PublisherFrontiers Research Foundation. The Journal's web site is located at http://www.frontiersin.org/pharmacology
Citation
Frontiers in Pharmacology, 2017, v. 8, p. 351:1-13 How to Cite?
AbstractEmerging 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-β (CaMKK-β), 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-α inhibitor, which lead to autophagic induction through PKC-α 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.
Persistent Identifierhttp://hdl.handle.net/10722/243005
ISSN
2017 Impact Factor: 3.831
2015 SCImago Journal Rankings: 1.845
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWong, VKW-
dc.contributor.authorZeng, W-
dc.contributor.authorChen, J-
dc.contributor.authorYao, J-
dc.contributor.authorLeung, ELH-
dc.contributor.authorWang, QQ-
dc.contributor.authorChiu, P-
dc.contributor.authorKo, BCB-
dc.contributor.authorLaw, BYK-
dc.date.accessioned2017-08-25T02:48:37Z-
dc.date.available2017-08-25T02:48:37Z-
dc.date.issued2017-
dc.identifier.citationFrontiers in Pharmacology, 2017, v. 8, p. 351:1-13-
dc.identifier.issn1663-9812-
dc.identifier.urihttp://hdl.handle.net/10722/243005-
dc.description.abstractEmerging 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-β (CaMKK-β), 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-α inhibitor, which lead to autophagic induction through PKC-α 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.-
dc.languageeng-
dc.publisherFrontiers Research Foundation. The Journal's web site is located at http://www.frontiersin.org/pharmacology-
dc.relation.ispartofFrontiers in Pharmacology-
dc.rightsThis Document is Protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleTetrandrine, an activator of autophagy, induces autophagic cell death via PKC-α inhibition and mTOR-dependent mechanisms.-
dc.typeArticle-
dc.identifier.emailChiu, P: pchiu@hku.hk-
dc.identifier.authorityChiu, P=rp00680-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3389/fphar.2017.00351-
dc.identifier.hkuros274429-
dc.identifier.volume8-
dc.identifier.spage351:1-
dc.identifier.epage13-
dc.identifier.isiWOS:000402859100002-
dc.publisher.placeSwitzerland-

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