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

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.

• Authors: Tae-Jin Lee, Eun Mi Jung, Jung Tae Lee, Shin Kim, Jong-Wook Park, Kyeong Sook Choi, Taeg Kyu Kwon
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 5 Issue 11 Pg. 2737-46 (Nov 2006) ISSN: 1535-7163 [Print] United States
• PMID: 17121920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Sp1 Transcription Factor
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• X-Linked Inhibitor of Apoptosis Protein
• mithramycin A
• Caspases
• Plicamycin

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Breast Neoplasms (metabolism)
• Carcinoma, Renal Cell (metabolism)
• Caspases (metabolism)
• Colonic Neoplasms (metabolism)
• Down-Regulation
• Female
• HT29 Cells
• Humans
• Male
• Plicamycin (analogs & derivatives, pharmacology)
• Promoter Regions, Genetic (drug effects)
• Sp1 Transcription Factor (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Tumor Cells, Cultured
• X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)