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 HRAS(G12V)-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 HRAS(G12V)-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 HRAS(G12V)-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.
Highlights
TNF-related apoptosis-inducing ligand (TRAIL) is a unique member of the TNF family, as it is the only known factor that induces apoptosis selectively in a large variety of tumor cells without affecting normal cells
TRAIL action is not limited to natural killer or natural killer T cells, as it acts ubiquitously in a cell autonomous and paracrine mode [8]
They are derived from normal human epithelial kidney (HEK), foreskin fibroblast (BJ), mammary epithelial (HMEC), and small airway lung epithelial (SALE) cells, respectively
Summary
TNF-related apoptosis-inducing ligand (TRAIL) is a unique member of the TNF family, as it is the only known factor that induces apoptosis selectively in a large variety of tumor cells without affecting normal cells. Unlike other members of this family, human TRAIL interacts with a complex system of receptors, comprising the 2 death-inducing receptors DR4 and DR5, 2 potentially antiapoptotic decoy receptors DcR1 and DcR2, and a soluble receptor osteoprotegerin. TRAIL plays a pivotal role in the innate immune system. Consistent with its role as cytokine, TRAIL is expressed in several types of immune cells and is crucial for tumor surveillance [3, 4]. TRAIL suppressed spontaneous tumor formation in mice that possess only one functional p53 allele [7]. TRAIL action is not limited to natural killer or natural killer T cells, as it acts ubiquitously in a cell autonomous and paracrine mode [8]
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