Hypoxia-induced decoy receptor 2 gene expression is regulated via a hypoxia-inducible factor 1alpha-mediated mechanism.
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 1alpha played a crucial role in regulating the transcription of DcR2, but that neither p53 nor NF-kappaB 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.
Pei
Guo-Ting
GT
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Wu
Chi-Wei
CW
Lin
Wan-Wan
WW
D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053221:TNF-Related Apoptosis-Inducing Ligand; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors