TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell death

Abstract

We have identified TNFSF10 (TRAIL) as a p53-transcriptional target gene. There are two p53 DNA-binding sites in the human TNFSF10 promoter region, at 346 and 625 bp upstream of the transcription start site. A human p53-expressing adenovirus (Ad-p53) induced TRAIL mRNA and protein expression in HCT116 p53-/- human colon cancer cells. A human TRAIL-promoter reporter assay showed increased luciferase activity with the promoter vector that contains two p53 DNA-binding motifs,following Ad-p53 infection, compared to the control adenovirus infection. Using HCT116 cells, gene silencing of TNFSF10 by siRNA suppressed caspase 3 and 7 activity, even after treatment with the DNA-damaging chemotherapeutic agent adriamycin. TRAIL protein expression was elevated in adriamycin-treated breast cancer cells. In vivo, TRAIL expression was induced in mouse natural killer cells at 24 hours after systemic treatment with 5-Fluorouracil. p53-dependent TRAIL induction in natural killer cells after chemotherapy exposure provides a link between the tumor suppressor p53 and the host immune response during cancer therapy as well as a paracrine-mediated cell-extrinsic death response. Our findings provide new mechanistic insights into the signaling of p53-dependent cell death and tumor suppression, including the involvement of the host immune system and natural killer cells in vivo in the anti-tumor efficacy of chemotherapy.

Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed

“…We however detected upregulated death receptors, Fas and TRAIL receptor molecules, as reported previously. 16 These biochemical data suggested that Ad-p53 activated primarily the extrinsic pathway in contrast to CDDP treatments that activated the both pathways. Shinoura et al 17 demonstrated enhanced apoptosis by a combination of Ad-p53 and forced expressions of Apaf-1 and caspase-9, suggesting less involvement of the intrinsic pathways by Ad-p53.…”

Adenoviral mediated transduction of adenoid cystic carcinoma by human TRAIL gene driven with hTERT tumor specific promoter induces apoptosis

“…35,36 Recently, some researches developed targeted or inducible vector systems. [37][38][39][40][41][42] Herein, we used the E1 deleted vector and tumor cell specific promoter, hTERT, to drive the hTRAIL gene expression.…”

Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity

“…1, 4-6). Despite its regulation by p53 (7), the apoptogenic action of TRAIL or other member of the TNF family (8) is largely independent of p53 integrity (9).…”