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Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites.

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dc.contributor.authorLee, TJ-
dc.contributor.authorJung, EM-
dc.contributor.authorLee, JT-
dc.contributor.authorKim, S-
dc.contributor.authorPark, JW-
dc.contributor.authorChoi, KS-
dc.contributor.authorKwon, TK-
dc.date.accessioned2011-04-20T05:35:54Z-
dc.date.available2011-04-20T05:35:54Z-
dc.date.issued2006-
dc.identifier.issn1535-7163-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/2400-
dc.description.abstractMithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we investigated the combined effect of mithramycin A and tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) on apoptosis of cancer cells. In Caki renal cancer cells, which are resistant to TRAIL, cotreatment with subtoxic doses of mithramycin A and TRAIL resulted in a marked increase in apoptosis. This combined treatment was also cytotoxic to Caki cells overexpressing Bcl-2 but not to normal mesengial cells. Moreover, apoptosis by the combined treatment with mithramycin A and TRAIL was dramatically induced in various cancer cell types, thus offering an attractive strategy for safely treating malignant tumors. Mithramycin A-stimulated TRAIL-induced apoptosis was blocked by pretreatment with the broad caspase inhibitor zVAD-fmk or Crm-A overexpression, showing its dependence on caspases. We found that mithramycin A selectively down-regulated XIAP protein levels in various cancer cells. Luciferase reporter assay and the chromatin immunoprecipitation assay using the XIAP promoter constructs show that mithramycin A down-regulates the transcription of XIAP gene through inhibition of Sp1 binding to its promoter. Although XIAP overexpression significantly attenuated apoptosis induced by mithramycin A plus TRAIL, suppression of XIAP expression by transfection with its small interfering RNA prominently enhanced TRAIL-induced apoptosis. We present here for the first time that mithramycin A-induced suppression of XIAP transcription plays a critical role in the recovery of TRAIL sensitivity in various cancer cells.-
dc.language.isoen-
dc.subject.MESHAntineoplastic Combined Chemotherapy Protocols-
dc.subject.MESHApoptosis-
dc.subject.MESHBinding Sites-
dc.subject.MESHBreast Neoplasms-
dc.subject.MESHCarcinoma, Renal Cell-
dc.subject.MESHCaspases-
dc.subject.MESHColonic Neoplasms-
dc.subject.MESHDown-Regulation-
dc.subject.MESHFemale-
dc.subject.MESHHT29 Cells-
dc.subject.MESHHumans-
dc.subject.MESHMale-
dc.subject.MESHPlicamycin-
dc.subject.MESHPromoter Regions, Genetic-
dc.subject.MESHSp1 Transcription Factor-
dc.subject.MESHTNF-Related Apoptosis-Inducing Ligand-
dc.subject.MESHTumor Cells, Cultured-
dc.subject.MESHX-Linked Inhibitor of Apoptosis Protein-
dc.titleMithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites.-
dc.typeArticle-
dc.identifier.pmid17121920-
dc.identifier.urlhttp://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17121920-
dc.contributor.affiliatedAuthor최, 경숙-
dc.type.localJournal Papers-
dc.identifier.doi10.1158/1535-7163.MCT-06-0426-
dc.citation.titleMolecular cancer therapeutics-
dc.citation.volume5-
dc.citation.number11-
dc.citation.date2006-
dc.citation.startPage2737-
dc.citation.endPage2746-
dc.identifier.bibliographicCitationMolecular cancer therapeutics, 5(11). : 2737-2746, 2006-
dc.identifier.eissn1538-8514-
dc.relation.journalidJ015357163-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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