American Association for Cancer Research
Browse
- No file added yet -

Supplementary Figure 1E-J from Transformation-Dependent Silencing of Tumor-Selective Apoptosis-Inducing TRAIL by DNA Hypermethylation Is Antagonized by Decitabine

Download (347.32 kB)
journal contribution
posted on 2023-04-03, 13:20 authored by Per Lund, Irina Kotova, Valérie Kedinger, Harshal Khanwalkar, Emilie Voltz, William C. Hahn, Hinrich Gronemeyer
Supplementary Figure 1E-J from Transformation-Dependent Silencing of Tumor-Selective Apoptosis-Inducing TRAIL by DNA Hypermethylation Is Antagonized by Decitabine

History

ARTICLE ABSTRACT

TNF-related apoptosis-inducing ligand (TRAIL) kills tumor cells selectively. We asked how emerging tumor cells escape elimination by TRAIL and how tumor-specific killing by TRAIL could then be restored. We found that TRAIL expression is consistently downregulated in HRASG12V-transformed cells in stepwise tumorigenesis models derived from four different tissues due to DNA hypermethylation of CpG clusters within the TRAIL promoter. Decitabine de-silenced TRAIL, which remained inducible by interferon, while induction of TRAIL by blocking the HRASG12V-activated mitogen-activated protein kinase pathway was subordinated to epigenetic silencing. Decitabine induced apoptosis through upregulation of endogenous TRAIL in cooperation with favorable regulation of key players acting in TRAIL-mediated apoptosis. Apoptosis induction by exogenously added TRAIL was largely increased by decitabine. In vivo treatment of xenografted human HRASG12V-transformed human epithelial kidney or syngenic mice tumors by decitabine blocked tumor growth induced TRAIL expression and apoptosis. Our results emphasize the potential of decitabine to enhance TRAIL-induced apoptosis in tumors and thus provide a rationale for combination therapies with decitabine to increase tumor-selective apoptosis. Mol Cancer Ther; 10(9); 1611–23. ©2011 AACR.

Usage metrics

    Molecular Cancer Therapeutics

    Categories

    Keywords

    CarcinogenesisAnimal models of carcinogenesisTumor initiation and promotionCell Death And SenescenceEffectors of apoptosisFas/tumor necrosis factor receptor familyDrug MechanismsCellular responses to anticancer drugsDrug-mediated stimulation of cell death pathwaysEpigeneticsGenome BiologySilencing and reactivation of gene expressionProgression, Invasion & MetastasisTumor progression

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC