15-Deoxy-Δ12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: Involvement ofreactive oxygen species and C/EBP homologous transcription factor gene transcription
Journal
Molecular Cancer Therapeutics
Journal Volume
7
Journal Issue
10
Pages
3429-3440
Date Issued
2008
Author(s)
Abstract
Although 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) was reported to up-regulate death receptor 5 (DR5) protein expression and sensitize TRAIL-induced cytotoxicity, its action mechanism remains unclear. Using HCT116 colon cancer cells, we found that sensitization of TRAIL-induced cytotoxicity by 15dPGJ2 resulted from up-regulation of DR5 via gene transcription but was not associated with PPAR-γ activation. Moreover, 15dPGJ2 induced GRP78, XBP1, and C/EBP homologous transcription factor (CHOP) expression in HCT116 cells, confirming that 15dPGJ2 is an endoplasmic reticulum stress inducer. Knockdown of the CHOP gene by siRNA attenuated DR5 up-regulation and the sensitized cytotoxicity in colon cancer HCT116 and SW480. With deletion plasmids of DR5 promoters, we found that the CHOP-binding site was involved in activating the DR5 gene by 15dPGJ2. A mechanistic study showed the contributions of reactive oxygen species (ROS) and intracellular calcium in CHOP and DR5 gene up-regulation. 15dPGJ2 was also found to induce DR5 in two prostate cancer cell lines, LNCaP and PC3. Although in LNCaP DR5 up-regulation was accompanied by CHOP expression by 15dPGJ2, no significant increase in CHOP expression or DR5 promoter activity was observed in PC3 cells. Intriguingly, 15dPGJ2 induced ROS and calcium production in PC3 cells. This inability to induce CHOP was not due to the p53-null in PC3 cells, as similar extents of increase in CHOP protein were found due to 15dPGJ 2 in both wild-type and p53-null HCT116 cells. In summary, the effect of up-regulation of DR5 by 15dPGJ2 in colon cancer cells is independent of PPAR-γ and p53 but relies on CHOP induction through gene transcription involving ROS and calcium. Copyright ? 2008 American Association for Cancer Research.
SDGs
Other Subjects
15 deoxy delta12,14 prostaglandin J2; c ebp homologous transcription factor; calcium; death receptor 5; glucose regulated protein 78; peroxisome proliferator activated receptor gamma; protein p53; reactive oxygen metabolite; small interfering RNA; transcription factor; tumor necrosis factor related apoptosis inducing ligand; unclassified drug; X box binding protein 1; 15 deoxy delta(12,14) prostaglandin J2; 15-deoxy-delta(12,14)-prostaglandin J2; calcium; drug derivative; growth arrest and DNA damage inducible protein 153; peroxisome proliferator activated receptor gamma; prostaglandin D2; protein p53; tumor necrosis factor related apoptosis inducing ligand; tumor necrosis factor related apoptosis inducing ligand receptor; article; binding site; c ebp homologous transcription factor gene; calcium cell level; cancer cell; cell strain LNCaP; colon cancer; controlled study; cytotoxicity; dr5 gene; gene; gene expression; genetic transcription; human; human cell; male; nucleotide sequence; plasmid; priority journal; prostate cancer; upregulation; cell death; cell strain HCT116; colon tumor; drug effect; drug screening; endoplasmic reticulum; gene expression regulation; genetics; intracellular space; metabolism; pathology; signal transduction; upregulation; Calcium; Cell Death; Colonic Neoplasms; Drug Screening Assays, Antitumor; Endoplasmic Reticulum; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Intracellular Space; PPAR gamma; Prostaglandin D2; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Transcription, Genetic; Tumor Suppressor Protein p53; Up-Regulation
Type
journal article