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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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Author(s)
김신박종욱권택규
Alternative Author(s)
Kim, ShinPark, Jong WookKwon, Taeg Kyu
Publication Year
2006
Abstract
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-α–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. [Mol Cancer Ther 2006;5(11):2737–46]
Keywords: Mithramycin A; TRAIL; apoptosis; XIAP
Department
Dept. of Immunology (면역학)
Institute for Medical Science (의과학연구소)
Publisher
School of Medicine
Citation
Molecular Cancer Therapeutics, Vol.5(11) : 2737-2746, 2006
Type
Article
ISSN
1535-7163
DOI
10.1158/1535-7163.MCT-06-0426
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/33439
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