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Article: Fangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells

TitleFangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells
Authors
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
Citation
British Journal Of Pharmacology, 2011, v. 164 n. 2 B, p. 731-742 How to Cite?
Abstract
BACKGROUND 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.
Persistent Identifierhttp://hdl.handle.net/10722/138136
ISSN
2013 Impact Factor: 4.990
2013 SCImago Journal Rankings: 2.253
PubMed Central ID
ISI Accession Number ID
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.

References

 

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
DC FieldValueLanguage
dc.contributor.authorWang, Nen_HK
dc.contributor.authorPan, Wen_HK
dc.contributor.authorZhu, Men_HK
dc.contributor.authorZhang, Men_HK
dc.contributor.authorHao, Xen_HK
dc.contributor.authorLiang, Gen_HK
dc.contributor.authorFeng, Yen_HK
dc.date.accessioned2011-08-26T14:41:18Z-
dc.date.available2011-08-26T14:41:18Z-
dc.date.issued2011en_HK
dc.identifier.citationBritish Journal Of Pharmacology, 2011, v. 164 n. 2 B, p. 731-742en_HK
dc.identifier.issn0007-1188en_HK
dc.identifier.urihttp://hdl.handle.net/10722/138136-
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.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1en_HK
dc.relation.ispartofBritish Journal of Pharmacologyen_HK
dc.rightsBritish Journal of Pharmacology. Copyright © John Wiley & Sons Ltd.-
dc.subjectAMPKen_HK
dc.subjectautophagyen_HK
dc.subjectfangchinolineen_HK
dc.subjecthepatocellular carcinomaen_HK
dc.subjectp53en_HK
dc.subjectsestrin2en_HK
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.titleFangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailFeng, Y: yfeng@hku.hken_HK
dc.identifier.authorityFeng, Y=rp00466en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1111/j.1476-5381.2011.01349.xen_HK
dc.identifier.pmid21418191en_HK
dc.identifier.pmcidPMC3188903-
dc.identifier.scopuseid_2-s2.0-80052227790en_HK
dc.identifier.hkuros191219en_US
dc.identifier.hkuros208642-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052227790&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume164en_HK
dc.identifier.issue2 Ben_HK
dc.identifier.spage731en_HK
dc.identifier.epage742en_HK
dc.identifier.eissn1476-5381-
dc.identifier.isiWOS:000294367700028-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridWang, N=35072317700en_HK
dc.identifier.scopusauthoridPan, W=53866850200en_HK
dc.identifier.scopusauthoridZhu, M=36706949300en_HK
dc.identifier.scopusauthoridZhang, M=16744796200en_HK
dc.identifier.scopusauthoridHao, X=36720561100en_HK
dc.identifier.scopusauthoridLiang, G=7202631197en_HK
dc.identifier.scopusauthoridFeng, Y=24467969600en_HK

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