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dc.contributor.authorStraza, Michael W.
dc.contributor.authorPaliwal, Seema
dc.contributor.authorKovi, Ramesh C.
dc.contributor.authorRajeshkumar, Barur R.
dc.contributor.authorTrenh, Peter
dc.contributor.authorParker, Daniel
dc.contributor.authorWhalen, Giles F.
dc.contributor.authorLyle, Stephen
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorGrossman, Steven R.
dc.date2022-08-11T08:08:00.000
dc.date.accessioned2022-08-23T15:38:47Z
dc.date.available2022-08-23T15:38:47Z
dc.date.issued2010-09-15
dc.date.submitted2011-11-22
dc.identifier.citationCell Cycle. 2010 Sep 15;9(18):3740-50. Epub 2010 Sep 8. <a href="http://dx.doi.org/10.4161/cc.9.18.12936">Link to article on publisher's site</a>
dc.identifier.issn1551-4005 (Linking)
dc.identifier.doi10.4161/cc.9.18.12936
dc.identifier.pmid20930544
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26009
dc.description.abstractThe CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=20930544&dopt=Abstract">Link to Article in PubMed</a>
dc.subjectAlcohol Oxidoreductases
dc.subjectAnimals
dc.subjectAntineoplastic Agents
dc.subjectApoptosis
dc.subjectApoptosis Regulatory Proteins
dc.subjectChromatin Immunoprecipitation
dc.subjectColonic Neoplasms
dc.subjectDNA-Binding Proteins
dc.subjectHCT116 Cells
dc.subjectHumans
dc.subjectMembrane Proteins
dc.subjectMethionine
dc.subjectMice
dc.subjectMice, Nude
dc.subjectRepressor Proteins
dc.subjectTransplantation, Heterologous
dc.subjectTumor Suppressor Protein p53
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectMicrobiology
dc.titleTherapeutic targeting of C-terminal binding protein in human cancer
dc.typeJournal Article
dc.source.journaltitleCell cycle (Georgetown, Tex.)
dc.source.volume9
dc.source.issue18
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1139&amp;context=bmp_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bmp_pp/139
dc.identifier.contextkey2367989
refterms.dateFOA2022-08-23T15:38:47Z
html.description.abstract<p>The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies.</p>
dc.identifier.submissionpathbmp_pp/139
dc.contributor.departmentDepartment of Medicine, Division of Hematology/Oncology
dc.contributor.departmentDepartment of Surgery
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentDepartment of Cancer Biology
dc.source.pages3740-50


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