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Research Articles: Therapeutics, Targets, and Development

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

¹ Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu, South Korea and ² Institute for Medical Sciences, Ajou University School of Medicine, Suwon, South Korea

Requests for reprints: Taeg Kyu Kwon, Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea. Phone: 82-53-250-7846; Fax: 82-53-250-7074. E-mail: kwontk{at}dsmc.or.kr

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-–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]

Grant support: Korea Science and Engineering Foundation (Medical Research Council at Keimyung University) grants R13-2002-028-03001-0 and R01-2005-000-10786-0 and Korea Research Foundation grant KRF-2005-070-C00100.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: T-J. Lee and E. Mi Jung contributed equally to this work.

Received 7/20/06; accepted 9/11/06.

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