Hypoxia inducing factor-1alpha regulates tumor necrosis factor-related apoptosis-inducing ligand sensitivity in tumor cells exposed to hypoxia.
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.
Jeong
Jae-Kyo
JK
Center for Healthcare Technology Development, Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, South Korea.
Moon
Myung-Hee
MH
Seo
Jae-Suk
JS
Seol
Jae-Won
JW
Park
Sang-Youel
SY
Lee
You-Jin
YJ
D000693:Anaerobiosis; D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D053221:TNF-Related Apoptosis-Inducing Ligand; D010100:Oxygen