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Enzastaurin, a protein kinase C beta inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells

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dc.contributor.authorLee, Keun-Wook-
dc.contributor.authorKim, Sang Gyun-
dc.contributor.authorKim, Hwang-Phill-
dc.contributor.authorKwon, Euna-
dc.contributor.authorYou, Jiran-
dc.contributor.authorChoi, Hyung-Jun-
dc.contributor.authorPark, Jung-Hyun-
dc.contributor.authorKang, Byeong-Cheol-
dc.contributor.authorIm, Seock-Ah-
dc.contributor.authorKim, Tae-You-
dc.contributor.authorKim, Woo Ho-
dc.contributor.authorBang, Yung-Jue-
dc.date.accessioned2010-01-12T05:50:33Z-
dc.date.available2010-01-12T05:50:33Z-
dc.date.issued2008-03-15-
dc.identifier.citationCancer Res. 2008 Mar 15;68(6):1916-26.en
dc.identifier.issn1538-7445 (Electronic)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18339873-
dc.identifier.urihttp://hdl.handle.net/10371/29694-
dc.description.abstractActivation of protein kinase C (PKC) has been implicated in gastric carcinogenesis. Enzastaurin is an oral ATP-competitive inhibitor of the PKC beta isozyme. Although enzastaurin was initially advanced to the clinic based on its antiangiogenic activity, it is also known to have a direct effect on a variety of human cancer cells, inducing apoptosis by inhibiting the Akt signal pathway. However, data on enzastaurin for gastric cancer are limited. Therefore, this study was performed to assess the antitumor activity of enzastaurin on gastric cancer cells and to investigate the underlying antitumor mechanisms. Enzastaurin suppressed the proliferation of cultured gastric cancer cells and the growth of gastric carcinoma xenografts. Enzastaurin did not have an effect on gastric cancer cell cycle progression; however, it had a direct apoptosis-inducing effect through the caspase-mediated mitochondrial pathway. Glycogen synthase kinase 3beta phosphorylation, a reliable pharmacodynamic marker of enzastaurin activity, and Akt phosphorylation were both decreased after treatment with enzastaurin. Although the p90 ribosomal S6 kinase (Rsk) was also dephosphorylated, Erk phosphorylation was not affected in the enzastaurin-treated gastric cancer cells. Enzastaurin activated Bad, one of the Bcl-2 proapoptotic proteins, through dephosphorylation at Ser(112), and depletion of Bad activity resulted in resistance to enzastaurin-induced apoptosis and cytotoxicity in gastric cancer cells. These data suggest that enzastaurin induces apoptosis through Rsk-mediated and Bad-mediated pathways, besides inhibiting the Akt signal cascade. Furthermore, enzastaurin had synergistic or additive effects when combined with 5-fluorouracil, cisplatin, paclitaxel, or irinotecan. These results warrant further clinical investigation of enzastaurin for gastric cancer treatment.en
dc.language.isoen-
dc.publisherAmerican Association for Cancer Researchen
dc.subjectAnimalsen
dc.subjectAntineoplastic Combined Chemotherapy Protocols/pharmacologyen
dc.subjectApoptosis/*drug effects/physiologyen
dc.subjectCell Cycle/physiologyen
dc.subjectCell Growth Processes/drug effectsen
dc.subjectCell Line, Tumoren
dc.subjectFemaleen
dc.subjectHumansen
dc.subjectIndoles/administration & dosage/*pharmacologyen
dc.subjectMiceen
dc.subjectMice, Nudeen
dc.subjectMitochondria/drug effects/physiologyen
dc.subjectPhosphorylation/drug effectsen
dc.subjectProtein Kinase C/*antagonists & inhibitors/metabolismen
dc.subjectProtein Kinase Inhibitors/pharmacologyen
dc.subjectProto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolismen
dc.subjectRibosomal Protein S6 Kinases, 90-kDa/*metabolismen
dc.subjectSignal Transduction/drug effectsen
dc.subjectStomach Neoplasms/*drug therapy/metabolism/pathologyen
dc.subjectXenograft Model Antitumor Assaysen
dc.subjectbcl-Associated Death Protein/*metabolismen
dc.titleEnzastaurin, a protein kinase C beta inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cellsen
dc.typeArticleen
dc.contributor.AlternativeAuthor이근욱-
dc.contributor.AlternativeAuthor김상균-
dc.contributor.AlternativeAuthor김황필-
dc.contributor.AlternativeAuthor권은아-
dc.contributor.AlternativeAuthor최현준-
dc.contributor.AlternativeAuthor박정현-
dc.contributor.AlternativeAuthor강병철-
dc.contributor.AlternativeAuthor임석아-
dc.contributor.AlternativeAuthor김태유-
dc.contributor.AlternativeAuthor김우호-
dc.contributor.AlternativeAuthor방영주-
dc.identifier.doi10.1158/0008-5472.CAN-07-3195-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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