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Article: Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death

TitleInhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death
Authors
Keywordsc-Met tyrosine kinase inhibitor
NADPH
TIGAR
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2011, v. 30 n. 9, p. 1127-1134 How to Cite?
Abstractc-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers. © 2011 Macmillan Publishers Limited All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/137197
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council, Hong Kong Government471607
Head and Neck SPOREP50 CA097007
CCSGP30CA16672
2006.1.027
2007.1.025
2009.1.012
Funding Information:

We would like to thank Amgen, Inc. (USA) for the kind provision of the novel c-Met tyrosine kinase inhibitor, AM7. This study was supported by Research Grant Council, Hong Kong Government (471607) and Direct Grants for Research (2006.1.027; 2007.1.025; 2009.1.012) to VWYL. GBM is supported by Head and Neck SPORE P50 CA097007 and CCSG grant P30CA16672.

References

 

DC FieldValueLanguage
dc.contributor.authorLui, VWYen_HK
dc.contributor.authorWong, EYLen_HK
dc.contributor.authorHo, Ken_HK
dc.contributor.authorNg, PKSen_HK
dc.contributor.authorLau, CPYen_HK
dc.contributor.authorTsui, SKWen_HK
dc.contributor.authorTsang, CMen_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorCheng, SHen_HK
dc.contributor.authorNg, MHLen_HK
dc.contributor.authorNg, YKen_HK
dc.contributor.authorLam, EKYen_HK
dc.contributor.authorHong, Ben_HK
dc.contributor.authorLo, KWen_HK
dc.contributor.authorMok, TSKen_HK
dc.contributor.authorChan, ATCen_HK
dc.contributor.authorMills, GBen_HK
dc.date.accessioned2011-08-26T14:18:37Z-
dc.date.available2011-08-26T14:18:37Z-
dc.date.issued2011en_HK
dc.identifier.citationOncogene, 2011, v. 30 n. 9, p. 1127-1134en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137197-
dc.description.abstractc-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers. © 2011 Macmillan Publishers Limited All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subjectc-Met tyrosine kinase inhibitoren_HK
dc.subjectNADPHen_HK
dc.subjectTIGARen_HK
dc.subject.meshIndoles - pharmacology-
dc.subject.meshIntracellular Signaling Peptides and Proteins - genetics-
dc.subject.meshNADP - biosynthesis-
dc.subject.meshNasopharyngeal Neoplasms - drug therapy - metabolism - pathology-
dc.subject.meshPiperazines - pharmacology-
dc.titleInhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell deathen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0950-9232&volume=30&issue=9&spage=1127&epage=1134&date=2011&atitle=Inhibition+of+c-Met+downregulates+TIGAR+expression+and+reduces+NADPH+production+leading+to+cell+death-
dc.identifier.emailTsao, SW:gswtsao@hkucc.hku.hken_HK
dc.identifier.authorityTsao, SW=rp00399en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/onc.2010.490en_HK
dc.identifier.pmid21057531-
dc.identifier.scopuseid_2-s2.0-79952283136en_HK
dc.identifier.hkuros191072en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952283136&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume30en_HK
dc.identifier.issue9en_HK
dc.identifier.spage1127en_HK
dc.identifier.epage1134en_HK
dc.identifier.isiWOS:000287964100011-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridLui, VWY=7004231347en_HK
dc.identifier.scopusauthoridWong, EYL=8234468400en_HK
dc.identifier.scopusauthoridHo, K=34971221500en_HK
dc.identifier.scopusauthoridNg, PKS=54393943700en_HK
dc.identifier.scopusauthoridLau, CPY=36608195100en_HK
dc.identifier.scopusauthoridTsui, SKW=35304176500en_HK
dc.identifier.scopusauthoridTsang, CM=24831236400en_HK
dc.identifier.scopusauthoridTsao, SW=7102813116en_HK
dc.identifier.scopusauthoridCheng, SH=7404681588en_HK
dc.identifier.scopusauthoridNg, MHL=35292609300en_HK
dc.identifier.scopusauthoridNg, YK=14825706500en_HK
dc.identifier.scopusauthoridLam, EKY=34968116400en_HK
dc.identifier.scopusauthoridHong, B=7202125896en_HK
dc.identifier.scopusauthoridLo, KW=7402101603en_HK
dc.identifier.scopusauthoridMok, TSK=7006561460en_HK
dc.identifier.scopusauthoridChan, ATC=13404833700en_HK
dc.identifier.scopusauthoridMills, GB=35379638300en_HK
dc.identifier.citeulike8229378-

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