Hypoxia inducing factor-1alpha regulates tumor necrosis factor-related apoptosis-inducing ligand sensitivity in tumor cells exposed to hypoxia.

Abstract

Hypoxia is a common environmental stress. Particularly, the center of rapidly-growing solid tumors is easily exposed to hypoxic conditions. Hypoxia is well known to attenuate the therapeutic response to radio and chemotherapies including tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) protein. HIF-1alpha is a critical mediator of the hypoxic response. However, little is known about the function of hypoxia-inducible factor-1alpha (HIF-1alpha) on hypoxic inhibition of TRAIL-mediated apoptosis. In this study, we investigated whether hypoxic inhibition of TRAIL-mediated apoptosis can be regulated by modulating HIF-1alpha protein. Hypoxia- and DEF-induced HIF-1alpha activation inhibited the TRAIL-mediated apoptosis in SK-N-SH, HeLa, A549 and SNU-638 cells. And also, HIF-1alpha inactivating reagents including DOX increased the sensitivity to TRAIL protein in tumor cells exposed to hypoxia. Furthermore, knock-down of HIF-1alpha using lentiviral RNA interference sensitized tumor cells to TRAIL-mediated cell death under hypoxic condition. Taken together, these results indicate that HIF-1alpha inactivation increased TRAIL sensitivity in hypoxia-induced TRAIL-resistant tumor cells and also suggest that HIF-1alpha inhibitors may have benefits in combination therapy with TRAIL against hypoxic tumor cells.

• Authors: Jae-Kyo Jeong, Myung-Hee Moon, Jae-Suk Seo, Jae-Won Seol, Sang-Youel Park, You-Jin Lee
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 399 Issue 3 Pg. 379-83 (Aug 27 2010) ISSN: 1090-2104 [Electronic] United States
• PMID: 20659427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Ligands
• TNF-Related Apoptosis-Inducing Ligand
• Oxygen

Topics

• Anaerobiosis
• Apoptosis
• Cell Hypoxia
• Cell Line, Tumor
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Ligands
• Neoplasms (drug therapy, metabolism)
• Oxygen (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)