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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

Cited 54 time in Web of Science Cited 56 time in Scopus
Authors
Lee, Keun-Wook; Kim, Sang Gyun; Kim, Hwang-Phill; Kwon, Euna; You, Jiran; Choi, Hyung-Jun; Park, Jung-Hyun; Kang, Byeong-Cheol; Im, Seock-Ah; Kim, Tae-You; Kim, Woo Ho; Bang, Yung-Jue
Issue Date
2008-03-15
Publisher
American Association for Cancer Research
Citation
Cancer Res. 2008 Mar 15;68(6):1916-26.
Keywords
AnimalsAntineoplastic Combined Chemotherapy Protocols/pharmacologyApoptosis/*drug effects/physiologyCell Cycle/physiologyCell Growth Processes/drug effectsCell Line, TumorFemaleHumansIndoles/administration & dosage/*pharmacologyMiceMice, NudeMitochondria/drug effects/physiologyPhosphorylation/drug effectsProtein Kinase C/*antagonists & inhibitors/metabolismProtein Kinase Inhibitors/pharmacologyProto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolismRibosomal Protein S6 Kinases, 90-kDa/*metabolismSignal Transduction/drug effectsStomach Neoplasms/*drug therapy/metabolism/pathologyXenograft Model Antitumor Assaysbcl-Associated Death Protein/*metabolism
Abstract
Activation 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.
ISSN
1538-7445 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18339873

http://hdl.handle.net/10371/29694
DOI
https://doi.org/10.1158/0008-5472.CAN-07-3195
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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