Hypoxia-induced decoy receptor 2 gene expression is regulated via a hypoxia-inducible factor 1α-mediated mechanism
Journal
Biochemical and Biophysical Research Communications
Journal Volume
391
Journal Issue
2
Pages
1274-1279
Date Issued
2010
Author(s)
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for anti-tumor therapy because of its high selectivity towards cancer cells. TRAIL has four major distinct receptors: DR4 and DR5 can recruit Fas-associated death domain protein to induce extrinsic death signal, while DcR1 and DcR2 are decoy receptors that can neutralize TRAIL toxicity by binding to TRAIL. Hypoxia is an important feature of solid tumors that renders tumor cells resistant to some chemotherapeutic agents, including TRAIL, and we therefore investigated the role of hypoxia in TRAIL receptor expression in human colon cancer cells. Hypoxia upregulated DcR2 protein expression in five different human colon cancer cell lines (HCT116, HT29, SW480, SW620, and WiDr). Flow cytometry analysis indicated that the increased DcR2 protein was expressed on the cell surface membrane. In contrast, hypoxia had no effect on DR4, DR5, or DcR1 protein levels. RT-PCR analysis suggested that this protein increase was the result of DcR2 gene transcription. Transcription factors were investigated using p53-null cells, pharmacological inhibitors, and a small interfering RNA approach. Our results demonstrated that hypoxia-inducible factor 1α played a crucial role in regulating the transcription of DcR2, but that neither p53 nor NF-κB contributed to this regulation. Moreover, TRAIL-induced, but not agonistic DR5 antibody-induced cell death was attenuated under hypoxic conditions. These results suggest that increased DcR2 protein levels might play a role in TRAIL resistance in solid tumors. ? 2009 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
decoy receptor 2; hypoxia inducible factor 1alpha; immunoglobulin enhancer binding protein; protein; protein p53; small interfering RNA; tumor necrosis factor related apoptosis inducing ligand; tumor necrosis factor related apoptosis inducing ligand receptor; unclassified drug; article; cancer cell culture; colon cancer; controlled study; flow cytometry; gene expression; gene expression regulation; human; human cell; hypoxia; null allele; priority journal; protein expression; reverse transcription polymerase chain reaction; Cell Hypoxia; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Promoter Regions, Genetic; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor Decoy Receptors
Type
journal article