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

Lee, TJ; Jung, EM; Lee, JT; Kim, S; Park, JW; Choi, KS; Kwon, TK
Molecular cancer therapeutics, 5(11):2737-2746, 2006
Journal Title
Molecular cancer therapeutics
Mithramycin 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.
MeSH terms
Antineoplastic Combined Chemotherapy Protocols/pharmacology*Apoptosis/drug effects*Binding SitesBreast Neoplasms/metabolismCarcinoma, Renal Cell/metabolismCaspases/metabolismColonic Neoplasms/metabolismDown-Regulation*FemaleHT29 CellsHumansMalePlicamycin/analogs & derivatives*Plicamycin/pharmacologyPromoter Regions, Genetic/drug effects*Sp1 Transcription Factor/metabolism*TNF-Related Apoptosis-Inducing Ligand/pharmacologyTumor Cells, CulturedX-Linked Inhibitor of Apoptosis Protein/genetics*X-Linked Inhibitor of Apoptosis Protein/metabolism
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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