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dc.contributor.authorGhosh, Jagadish C.
dc.contributor.authorAltieri, Dario C.
dc.date2022-08-11T08:09:59.000
dc.date.accessioned2022-08-23T16:51:07Z
dc.date.available2022-08-23T16:51:07Z
dc.date.issued2005-06-17
dc.date.submitted2008-06-18
dc.identifier.citationClin Cancer Res. 2005 Jun 15;11(12):4580-8. <a href="http://dx.doi.org/10.1158/1078-0432.CCR-04-2624">Link to article on publisher's site</a>
dc.identifier.issn1078-0432 (Print)
dc.identifier.doi10.1158/1078-0432.CCR-04-2624
dc.identifier.pmid15958644
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41798
dc.description.abstractPURPOSE: The restoration of checkpoint mechanisms may provide a rational anticancer approach, but the molecular circuitries of how this can be achieved therapeutically are poorly understood. A pivotal signaling network in colorectal cancer cells involves glycogen synthase kinase-3beta (GSK3beta), a multifunctional kinase whose role in tumor cell survival is not defined. EXPERIMENTAL DESIGN: We used molecular, genetic, and pharmacologic antagonists of GSK3beta in p53+/+ or p53-/- colorectal cancer cells. We monitored kinase activity in immunoprecipitation, protein expression by immunoblotting, and cell death by multiparametric flow cytometry. A xenograft colorectal cancer model was used to study antitumor activity in vivo. RESULTS: Treatment of p53+/+ colorectal cancer cells with pharmacologic inhibitors of GSK3beta resulted in sustained elevation of p53, with up-regulation of p21(Waf1/Cip1) and loss of survivin levels. Molecular targeting of GSK3beta by overexpression of a GSK3beta dominant-negative mutant, or acute-silencing of GSK3beta by RNA interference, reproduced the induction of transcriptionally active p53 in colorectal cancer cells. This pathway was recapitulated by deregulated Wnt/T-cell factor signaling, with elevation of the tumor suppressor p14ARF, and reduced expression of the p53 antagonist, MDM2. Rather than cell cycle arrest, GSK3beta blockade resulted in p53-dependent apoptosis, which was contributed by acute loss of survivin and inhibition of colorectal cancer growth in mice. CONCLUSIONS: Acute ablation of GSK3beta in colorectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth. This pathway may be exploited for rational treatment of colorectal cancer patients retaining wild-type p53.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15958644&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1158/1078-0432.CCR-04-2624
dc.subject*Apoptosis
dc.subjectBlotting, Western
dc.subjectCDC2 Protein Kinase
dc.subjectCell Cycle Proteins
dc.subjectColonic Neoplasms
dc.subjectCyclin-Dependent Kinase Inhibitor p21
dc.subjectCytoskeletal Proteins
dc.subjectGlycogen Synthase Kinase 3
dc.subjectHCT116 Cells
dc.subjectHumans
dc.subjectIndoles
dc.subjectMaleimides
dc.subjectMicrotubule-Associated Proteins
dc.subjectMutation
dc.subjectNeoplasm Proteins
dc.subjectNuclear Proteins
dc.subjectProto-Oncogene Proteins
dc.subjectProto-Oncogene Proteins c-mdm2
dc.subjectPurines
dc.subjectRNA Interference
dc.subjectTCF Transcription Factors
dc.subjectThiadiazoles
dc.subjectTrans-Activators
dc.subjectTranscription Factors
dc.subjectTransfection
dc.subjectTumor Suppressor Protein p14ARF
dc.subjectTumor Suppressor Protein p53
dc.subjectbeta Catenin
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleActivation of p53-dependent apoptosis by acute ablation of glycogen synthase kinase-3beta in colorectal cancer cells
dc.typeJournal Article
dc.source.journaltitleClinical cancer research : an official journal of the American Association for Cancer Research (6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine )
dc.source.volume11
dc.source.issue12
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/460
dc.identifier.contextkey533174
html.description.abstract<p>PURPOSE: The restoration of checkpoint mechanisms may provide a rational anticancer approach, but the molecular circuitries of how this can be achieved therapeutically are poorly understood. A pivotal signaling network in colorectal cancer cells involves glycogen synthase kinase-3beta (GSK3beta), a multifunctional kinase whose role in tumor cell survival is not defined. EXPERIMENTAL DESIGN: We used molecular, genetic, and pharmacologic antagonists of GSK3beta in p53+/+ or p53-/- colorectal cancer cells. We monitored kinase activity in immunoprecipitation, protein expression by immunoblotting, and cell death by multiparametric flow cytometry. A xenograft colorectal cancer model was used to study antitumor activity in vivo. RESULTS: Treatment of p53+/+ colorectal cancer cells with pharmacologic inhibitors of GSK3beta resulted in sustained elevation of p53, with up-regulation of p21(Waf1/Cip1) and loss of survivin levels. Molecular targeting of GSK3beta by overexpression of a GSK3beta dominant-negative mutant, or acute-silencing of GSK3beta by RNA interference, reproduced the induction of transcriptionally active p53 in colorectal cancer cells. This pathway was recapitulated by deregulated Wnt/T-cell factor signaling, with elevation of the tumor suppressor p14ARF, and reduced expression of the p53 antagonist, MDM2. Rather than cell cycle arrest, GSK3beta blockade resulted in p53-dependent apoptosis, which was contributed by acute loss of survivin and inhibition of colorectal cancer growth in mice. CONCLUSIONS: Acute ablation of GSK3beta in colorectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth. This pathway may be exploited for rational treatment of colorectal cancer patients retaining wild-type p53.</p>
dc.identifier.submissionpathoapubs/460
dc.contributor.departmentDepartment of Cancer Biology and Cancer Center
dc.source.pages4580-8


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