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Article: Fangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells
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TitleFangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells
 
AuthorsWang, N1
Pan, W3
Zhu, M1
Zhang, M3 4
Hao, X5 3
Liang, G2 3
Feng, Y1
 
KeywordsAMPK
autophagy
fangchinoline
hepatocellular carcinoma
p53
sestrin2
 
Issue Date2011
 
PublisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
 
CitationBritish Journal Of Pharmacology, 2011, v. 164 n. 2 B, p. 731-742 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1476-5381.2011.01349.x
 
AbstractBACKGROUND AND PURPOSE Fangchinoline is a novel anti-tumour agent with little known of its cellular and molecular mechanisms of action. Here we have investigated the mode of cell death induced by fangchinoline and its underlying mechanism in two human hepatocellular carcinoma cell lines, HepG2 and PLC/PRF/5. EXPERIMENTAL APPROACH Apoptosis and autophagy were monitored in fangchinoline-treated HepG2 and PLC/PRF/5 cells by histological methods. The signal transduction pathways involved in activation of autophagy were examined, using immunoblotting, real-time PCR and siRNA techniques. KEY RESULTS Fangchinoline did not induce apoptosis in HepG2 and PLC/PRF/5 cells but triggered, dose-dependently, autophagy, an alternative mode of cell death which may contribute to fangchinoline's anti-tumour action. Nuclear translocation of p53 was involved in induction of autophagy by fangchinoline, followed by selective transactivation of the autophagy-related gene sestrin2 and initiation of the autophagic process. Signalling by the AMP-activated protein kinase was also involved as a downstream target of sestrin2 and induced mTOR-independent autophagic cell death in both cell lines. siRNA for Atg 5 or pharmacological block of p53 abolished fangchinoline-induced autophagy and inhibition of autophagy switched cell death to apoptosis in these cells, suggesting that cell death is irreversible once autophagy is induced by fangchinoline. CONCLUSIONS AND IMPLICATIONS Fangchinoline is a highly specific agent inducing autophagic cell death in hepatocellular carcinoma cells with a novel mechanism, which elucidates the potential of fangchinoline to potentiate programmed cell death in cancer cells. © 2011 The British Pharmacological Society.
 
ISSN0007-1188
2013 Impact Factor: 4.990
2013 SCImago Journal Rankings: 2.253
 
DOIhttp://dx.doi.org/10.1111/j.1476-5381.2011.01349.x
 
PubMed Central IDPMC3188903
 
ISI Accession Number IDWOS:000294367700028
Funding AgencyGrant Number
research council of the University of Hong Kong10400413
10400699
Government-Matching Grant Scheme (fourth Phase)20740314
Science and Technology Department of Guizhou Province, ChinaQKHYSCN [2009]4010
QKHRCTD[2008]4008
Funding Information:

The study was financially supported by grants from the research council of the University of Hong Kong (Project Codes: 10400413 and 10400699), Government-Matching Grant Scheme (fourth Phase, Project Code: 20740314) and the Science and Technology Department of Guizhou Province, China (Project Code: QKHYSCN [2009]4010 and QKHRCTD[2008]4008). The authors are grateful to the support of Professors Yung-Chi Cheng, Sai-Wah Tsao, Yao Tong and Allan SY Lau. The authors would like to express thanks to Ms Oi Yee Chow, Ms Cindy Lee, Mr Keith Wong and Mr Freddy Tsang for their technical support. We also thank Professor Tamotsu Yoshimori for kindly providing GFP-LC3 plasmid.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorWang, N
 
dc.contributor.authorPan, W
 
dc.contributor.authorZhu, M
 
dc.contributor.authorZhang, M
 
dc.contributor.authorHao, X
 
dc.contributor.authorLiang, G
 
dc.contributor.authorFeng, Y
 
dc.date.accessioned2011-08-26T14:41:18Z
 
dc.date.available2011-08-26T14:41:18Z
 
dc.date.issued2011
 
dc.description.abstractBACKGROUND AND PURPOSE Fangchinoline is a novel anti-tumour agent with little known of its cellular and molecular mechanisms of action. Here we have investigated the mode of cell death induced by fangchinoline and its underlying mechanism in two human hepatocellular carcinoma cell lines, HepG2 and PLC/PRF/5. EXPERIMENTAL APPROACH Apoptosis and autophagy were monitored in fangchinoline-treated HepG2 and PLC/PRF/5 cells by histological methods. The signal transduction pathways involved in activation of autophagy were examined, using immunoblotting, real-time PCR and siRNA techniques. KEY RESULTS Fangchinoline did not induce apoptosis in HepG2 and PLC/PRF/5 cells but triggered, dose-dependently, autophagy, an alternative mode of cell death which may contribute to fangchinoline's anti-tumour action. Nuclear translocation of p53 was involved in induction of autophagy by fangchinoline, followed by selective transactivation of the autophagy-related gene sestrin2 and initiation of the autophagic process. Signalling by the AMP-activated protein kinase was also involved as a downstream target of sestrin2 and induced mTOR-independent autophagic cell death in both cell lines. siRNA for Atg 5 or pharmacological block of p53 abolished fangchinoline-induced autophagy and inhibition of autophagy switched cell death to apoptosis in these cells, suggesting that cell death is irreversible once autophagy is induced by fangchinoline. CONCLUSIONS AND IMPLICATIONS Fangchinoline is a highly specific agent inducing autophagic cell death in hepatocellular carcinoma cells with a novel mechanism, which elucidates the potential of fangchinoline to potentiate programmed cell death in cancer cells. © 2011 The British Pharmacological Society.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationBritish Journal Of Pharmacology, 2011, v. 164 n. 2 B, p. 731-742 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1476-5381.2011.01349.x
 
dc.identifier.doihttp://dx.doi.org/10.1111/j.1476-5381.2011.01349.x
 
dc.identifier.eissn1476-5381
 
dc.identifier.epage742
 
dc.identifier.hkuros191219
 
dc.identifier.hkuros208642
 
dc.identifier.isiWOS:000294367700028
Funding AgencyGrant Number
research council of the University of Hong Kong10400413
10400699
Government-Matching Grant Scheme (fourth Phase)20740314
Science and Technology Department of Guizhou Province, ChinaQKHYSCN [2009]4010
QKHRCTD[2008]4008
Funding Information:

The study was financially supported by grants from the research council of the University of Hong Kong (Project Codes: 10400413 and 10400699), Government-Matching Grant Scheme (fourth Phase, Project Code: 20740314) and the Science and Technology Department of Guizhou Province, China (Project Code: QKHYSCN [2009]4010 and QKHRCTD[2008]4008). The authors are grateful to the support of Professors Yung-Chi Cheng, Sai-Wah Tsao, Yao Tong and Allan SY Lau. The authors would like to express thanks to Ms Oi Yee Chow, Ms Cindy Lee, Mr Keith Wong and Mr Freddy Tsang for their technical support. We also thank Professor Tamotsu Yoshimori for kindly providing GFP-LC3 plasmid.

 
dc.identifier.issn0007-1188
2013 Impact Factor: 4.990
2013 SCImago Journal Rankings: 2.253
 
dc.identifier.issue2 B
 
dc.identifier.pmcidPMC3188903
 
dc.identifier.pmid21418191
 
dc.identifier.scopuseid_2-s2.0-80052227790
 
dc.identifier.spage731
 
dc.identifier.urihttp://hdl.handle.net/10722/138136
 
dc.identifier.volume164
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofBritish Journal of Pharmacology
 
dc.relation.referencesReferences in Scopus
 
dc.rightsBritish Journal of Pharmacology. Copyright © John Wiley & Sons Ltd.
 
dc.subject.meshAMP-Activated Protein Kinases - metabolism
 
dc.subject.meshCarcinoma, Hepatocellular - drug therapy - genetics - metabolism - pathology
 
dc.subject.meshLiver Neoplasms - drug therapy - genetics - metabolism - pathology
 
dc.subject.meshNuclear Proteins - genetics - metabolism
 
dc.subject.meshTumor Suppressor Protein p53 - metabolism
 
dc.subjectAMPK
 
dc.subjectautophagy
 
dc.subjectfangchinoline
 
dc.subjecthepatocellular carcinoma
 
dc.subjectp53
 
dc.subjectsestrin2
 
dc.titleFangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Guiyang College of Traditional Chinese Medicine
  3. Chinese Academy of Sciences
  4. Zunyi Medical College
  5. Kunming Institute of Botany Chinese Academy of Sciences