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Article: Rapamycin and CCI-779 inhibit the mammalian target of rapamycin signalling in hepatocellular carcinoma

TitleRapamycin and CCI-779 inhibit the mammalian target of rapamycin signalling in hepatocellular carcinoma
Authors
KeywordsCCI-779
Hepatocellular carcinoma
mTOR
p70S6K
Rapamycin
Tumour suppression
Issue Date2010
PublisherWiley-Blackwell Publishing, Inc.. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1478-3223&site=1
Citation
Liver International, 2010, v. 30 n. 1, p. 65-75 How to Cite?
AbstractBackground: The mammalian target of rapamycin (mTOR), which phosphorylates p70S6K and 4EBP1 and activates the protein translation process, is upregulated in cancers and its activation may be involved in cancer development. Aims: In this study, we investigated the tumour-suppressive effects of rapamycin and its new analogue CCI-779 on hepatocellular carcinoma (HCC). Methods: Rapamycin and its new analogue CCI-779 were applied to treat HCC cells. Cell proliferation, cell cycle profile and tumorigenicity were analysed. Results: In human HCCs, we observed frequent (67%, 37/55) overexpression of mTOR transcripts using real-time reverse transcriptasepolymerase chain reaction. Upon drug treatment, PLC/PRF/5 showed the greatest reduction in cell proliferation using the colony formation assay, as compared with HepG2, Hep3B and HLE. Rapamycin was a more potent antiproliferative agent than CCI-779 in HCC cell lines. Proliferation assays by cell counting showed that the IC50 value of rapamycin was lower than that of CCI-779 in PLC/PRF/5 cells. Furthermore, flow cytometric analysis showed that both drugs could arrest HCC cells in the G1 phase but did not induce apoptosis of these cells, suggesting that these mTOR inhibitors are cytostatic rather than cytotoxic. Upon rapamycin and CCI-779 treatment, the phosphorylation level of mTOR and p70S6K in HCC cell lines was significantly reduced, indicating that both drugs can suppress mTOR activity in HCC cells. In addition, both drugs significantly inhibited the growth of xenografts of PLC/PRF/5 cells in nude mice. Conclusions: Our findings indicate that rapamycin and its clinical analogue CCI-779 possess tumour-suppressive functions towards HCC cells. © 2009 John Wiley & Sons A/S.
Persistent Identifierhttp://hdl.handle.net/10722/126709
ISSN
2015 Impact Factor: 4.47
2015 SCImago Journal Rankings: 1.677
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants Council (RGC)HKU 1/06C
General Research Fund763607M
Funding Information:

The authors wish to thank Dr Tai-On Yau for the technical advice and assistance during the animal work. Financial support: This study was funded by a Hong Kong Research Grants Council (RGC) Collaborative Research Fund (HKU 1/06C) and General Research Fund (763607M). IOL Ng is a Loke Yew Professor in Pathology.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorHui, ICFen_HK
dc.contributor.authorTung, EKen_HK
dc.contributor.authorSze, KMFen_HK
dc.contributor.authorChing, YPen_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2010-10-31T12:43:58Z-
dc.date.available2010-10-31T12:43:58Z-
dc.date.issued2010en_HK
dc.identifier.citationLiver International, 2010, v. 30 n. 1, p. 65-75en_HK
dc.identifier.issn1478-3223en_HK
dc.identifier.urihttp://hdl.handle.net/10722/126709-
dc.description.abstractBackground: The mammalian target of rapamycin (mTOR), which phosphorylates p70S6K and 4EBP1 and activates the protein translation process, is upregulated in cancers and its activation may be involved in cancer development. Aims: In this study, we investigated the tumour-suppressive effects of rapamycin and its new analogue CCI-779 on hepatocellular carcinoma (HCC). Methods: Rapamycin and its new analogue CCI-779 were applied to treat HCC cells. Cell proliferation, cell cycle profile and tumorigenicity were analysed. Results: In human HCCs, we observed frequent (67%, 37/55) overexpression of mTOR transcripts using real-time reverse transcriptasepolymerase chain reaction. Upon drug treatment, PLC/PRF/5 showed the greatest reduction in cell proliferation using the colony formation assay, as compared with HepG2, Hep3B and HLE. Rapamycin was a more potent antiproliferative agent than CCI-779 in HCC cell lines. Proliferation assays by cell counting showed that the IC50 value of rapamycin was lower than that of CCI-779 in PLC/PRF/5 cells. Furthermore, flow cytometric analysis showed that both drugs could arrest HCC cells in the G1 phase but did not induce apoptosis of these cells, suggesting that these mTOR inhibitors are cytostatic rather than cytotoxic. Upon rapamycin and CCI-779 treatment, the phosphorylation level of mTOR and p70S6K in HCC cell lines was significantly reduced, indicating that both drugs can suppress mTOR activity in HCC cells. In addition, both drugs significantly inhibited the growth of xenografts of PLC/PRF/5 cells in nude mice. Conclusions: Our findings indicate that rapamycin and its clinical analogue CCI-779 possess tumour-suppressive functions towards HCC cells. © 2009 John Wiley & Sons A/S.en_HK
dc.languageengen_HK
dc.publisherWiley-Blackwell Publishing, Inc.. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=1478-3223&site=1en_HK
dc.relation.ispartofLiver Internationalen_HK
dc.rightsThe definitive version is available at www3.interscience.wiley.com-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectCCI-779en_HK
dc.subjectHepatocellular carcinomaen_HK
dc.subjectmTORen_HK
dc.subjectp70S6Ken_HK
dc.subjectRapamycinen_HK
dc.subjectTumour suppressionen_HK
dc.subject.meshAntibiotics, Antineoplastic - pharmacology-
dc.subject.meshCarcinoma, Hepatocellular - drug therapy - metabolism - pathology-
dc.subject.meshIntracellular Signaling Peptides and Proteins - antagonists and inhibitors - drug effects - metabolism-
dc.subject.meshLiver Neoplasms - drug therapy - metabolism - pathology-
dc.subject.meshProtein-Serine-Threonine Kinases - antagonists and inhibitors - drug effects - metabolism-
dc.titleRapamycin and CCI-779 inhibit the mammalian target of rapamycin signalling in hepatocellular carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1478-3223&volume=30&issue=1&spage=65&epage=75&date=2010&atitle=Rapamycin+and+CCI-779+inhibit+the+mammalian+target+of+rapamycin+signalling+in+hepatocellular+carcinomaen_HK
dc.identifier.emailChing, YP:ypching@hku.hken_HK
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1111/j.1478-3231.2009.02117.xen_HK
dc.identifier.pmid19845851-
dc.identifier.scopuseid_2-s2.0-73349090909en_HK
dc.identifier.hkuros173974en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-73349090909&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume30en_HK
dc.identifier.issue1en_HK
dc.identifier.spage65en_HK
dc.identifier.epage75en_HK
dc.identifier.isiWOS:000272443700008-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.identifier.scopusauthoridHui, ICF=35740368700en_HK
dc.identifier.scopusauthoridTung, EK=7003519614en_HK
dc.identifier.scopusauthoridSze, KMF=36828094800en_HK
dc.identifier.scopusauthoridChing, YP=7005431277en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK
dc.identifier.citeulike6335417-

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