Modulation of TRAIL-induced tumor cell apoptosis in a hypoxic environment

Hypoxia induces Hif-1α and selects for loss of wild-type p53 function, both of which can promote tumor cell survival. We evaluated the ability of TRAIL to induce apoptosis of human tumor cell lines exposed to hypoxia. H460 lung cancer cells express low levels of Hif-1α, stabilize wild-type p53 durin...

Full description

Saved in:
Bibliographic Details
Published in:Cancer biology & therapy 2005-10, Vol.4 (10), p.1068-1074
Main Authors: Mayes, Patrick A, Campbell, Latoya, Ricci, M Stacey, Plastaras, John P, Dicker, David T, El-Deiry, Wafik S
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Apoptosis Regulatory Proteins - antagonists & inhibitors
Apoptosis Regulatory Proteins - pharmacology
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cell Hypoxia - physiology
Cell Line, Tumor
Colonic Neoplasms - drug therapy
Cycle
Dose-Response Relationship, Drug
HCT116 Cells
Humans
Hypoxia-Inducible Factor 1 - genetics
Hypoxia-Inducible Factor 1 - metabolism
Landes
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - pharmacology
Organogenesis
Proteins
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - pharmacology
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Hypoxia induces Hif-1α and selects for loss of wild-type p53 function, both of which can promote tumor cell survival. We evaluated the ability of TRAIL to induce apoptosis of human tumor cell lines exposed to hypoxia. H460 lung cancer cells express low levels of Hif-1α, stabilize wild-type p53 during hypoxia, and undergo TRAIL-induced apoptosis. In U2OS osteosarcoma or PA1 ovarian teratocarcinoma cells, high levels of Hif-1α and low levels of stable p53 are detected during hypoxia, and cells undergo low levels of TRAIL-induced apoptosis as compared to H460 cells. H460 cells are sensitized to TRAIL-induced apoptosis, whereas U2OS are protected, and little apoptosis is observed in relatively TRAIL-resistant PA1 during hypoxia. Forced expression of Hif-1α is also surprisingly a potent inducer of apoptosis in wild-type p53 expressing H460 cells and further promotes TRAIL-induced apoptosis. TRAIL-sensitive wild-type p53-expressing HCT116 colon carcinoma cells modestly elevate Hif-1α levels and are equally or slightly more sensitive to TRAIL during hypoxia. In contrast, p53-null HCT116 have higher levels of Hif-1α during normoxia and are extremely sensitive to TRAIL, but are protected from TRAIL-induced apoptosis during hypoxia. We hypothesize that a hypoxic tumor microenvironment may alter sensitivity to TRAIL, which may be impacted by Hif-1α levels and p53 status. These findings suggest that particular attention to hypoxic regions of tumors and sensitizers to hypoxia-induced cell death may be required to optimize therapeutic combinations using TRAIL.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.4.10.2255