File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β 1-dependent pathway

TitleNovel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β 1-dependent pathway
Authors
KeywordsApoptosis
Cancer prevention
Cyclo-oxygenase-2
Gastric cancer
Protein kinase C
Issue Date2002
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2002, v. 21 n. 39, p. 6113-6122 How to Cite?
AbstractNonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-β 1, increased the expression of PKCδ and PKCη, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE 2 receptor antagonists could not reverse the inhibition effect on PKCβ 1 by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCβ 1 attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21 waf1/cip1. Inhibition of PKCβ 1-mediated overexpression of p21 waf1/cip1 partially reduced the anti-apoptotic effect of PKCβ 1. The down-regulation of PKCβ 1 provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCβ 1 act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.
Persistent Identifierhttp://hdl.handle.net/10722/162654
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorJiang, XHen_US
dc.contributor.authorLam, SKen_US
dc.contributor.authorLin, MCMen_US
dc.contributor.authorJiang, SHen_US
dc.contributor.authorKung, HFen_US
dc.contributor.authorSlosberg, EDen_US
dc.contributor.authorJae, WSen_US
dc.contributor.authorWeinstein, IBen_US
dc.contributor.authorWong, BCYen_US
dc.date.accessioned2012-09-05T05:22:06Z-
dc.date.available2012-09-05T05:22:06Z-
dc.date.issued2002en_US
dc.identifier.citationOncogene, 2002, v. 21 n. 39, p. 6113-6122en_US
dc.identifier.issn0950-9232en_US
dc.identifier.urihttp://hdl.handle.net/10722/162654-
dc.description.abstractNonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-β 1, increased the expression of PKCδ and PKCη, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE 2 receptor antagonists could not reverse the inhibition effect on PKCβ 1 by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCβ 1 attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21 waf1/cip1. Inhibition of PKCβ 1-mediated overexpression of p21 waf1/cip1 partially reduced the anti-apoptotic effect of PKCβ 1. The down-regulation of PKCβ 1 provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCβ 1 act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_US
dc.relation.ispartofOncogeneen_US
dc.subjectApoptosis-
dc.subjectCancer prevention-
dc.subjectCyclo-oxygenase-2-
dc.subjectGastric cancer-
dc.subjectProtein kinase C-
dc.subject.meshApoptosis - Drug Effectsen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshCell Cycle Proteins - Metabolismen_US
dc.subject.meshCyclin-Dependent Kinase Inhibitor P21en_US
dc.subject.meshCyclin-Dependent Kinase Inhibitor P27en_US
dc.subject.meshCyclins - Genetics - Metabolismen_US
dc.subject.meshCyclooxygenase Inhibitors - Pharmacologyen_US
dc.subject.meshDna, Antisense - Pharmacologyen_US
dc.subject.meshDown-Regulationen_US
dc.subject.meshGenes, Myc - Physiologyen_US
dc.subject.meshHumansen_US
dc.subject.meshIsoenzymes - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshProstaglandins - Pharmacologyen_US
dc.subject.meshProtein Kinase C - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshProto-Oncogene Proteins - Metabolismen_US
dc.subject.meshProto-Oncogene Proteins C-Bcl-2 - Metabolismen_US
dc.subject.meshPyrazoles - Pharmacologyen_US
dc.subject.meshReceptors, Prostaglandin E - Metabolismen_US
dc.subject.meshStomach Neoplasms - Drug Therapy - Enzymology - Pathologyen_US
dc.subject.meshSulfonamides - Pharmacologyen_US
dc.subject.meshTransfectionen_US
dc.subject.meshTumor Cells, Cultured - Drug Effects - Enzymology - Metabolismen_US
dc.subject.meshTumor Suppressor Protein P53 - Metabolismen_US
dc.subject.meshTumor Suppressor Proteins - Metabolismen_US
dc.subject.meshBcl-2-Associated X Proteinen_US
dc.titleNovel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β 1-dependent pathwayen_US
dc.typeArticleen_US
dc.identifier.emailLin, MCM:mcllin@hkucc.hku.hken_US
dc.identifier.emailWong, BCY:bcywong@hku.hken_US
dc.identifier.authorityLin, MCM=rp00746en_US
dc.identifier.authorityWong, BCY=rp00429en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/sj.onc.1205778en_US
dc.identifier.pmid12203123-
dc.identifier.scopuseid_2-s2.0-0037026663en_US
dc.identifier.hkuros82619-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0037026663&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume21en_US
dc.identifier.issue39en_US
dc.identifier.spage6113en_US
dc.identifier.epage6122en_US
dc.identifier.isiWOS:000177671300014-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridJiang, XH=36089034900en_US
dc.identifier.scopusauthoridLam, SK=7402279473en_US
dc.identifier.scopusauthoridLin, MCM=7404816359en_US
dc.identifier.scopusauthoridJiang, SH=7404453122en_US
dc.identifier.scopusauthoridKung, HF=7402514190en_US
dc.identifier.scopusauthoridSlosberg, ED=6604090681en_US
dc.identifier.scopusauthoridJae, WS=6602763136en_US
dc.identifier.scopusauthoridWeinstein, IB=36048534800en_US
dc.identifier.scopusauthoridWong, BCY=7402023340en_US

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats