24 218

Cited 54 times in

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

Authors
Lee, TJ; Jung, EM; Lee, JT; Kim, S; Park, JW; Choi, KS; Kwon, TK
Citation
Molecular cancer therapeutics, 5(11):2737-2746, 2006
Journal Title
Molecular cancer therapeutics
ISSN
1535-71631538-8514
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-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
DOI
10.1158/1535-7163.MCT-06-0426
PMID
17121920
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
최경숙
Full Text Link
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse