Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin
A solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced...
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doaj-45331def76fb44fb9ec7f98fb20e67b62020-11-25T00:56:47ZengMDPI AGInternational Journal of Molecular Sciences1422-00672014-07-01157119411195610.3390/ijms150711941ijms150711941Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through MelatoninYou-Jin Lee0Ju-Hee Lee1Ji-Hong Moon2Sang-Youel Park3Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, KoreaBiosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, KoreaBiosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, KoreaBiosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, KoreaA solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell apoptosis under hypoxic conditions. Melatonin inhibits cell proliferation in many cancer types and induces apoptosis in some particular cancer types. Here, we examined the effects of melatonin on hypoxic resistant cells against TRAIL-induced apoptosis and the possible mechanisms of melatonin in the hypoxic response. Melatonin treatment increased TRAIL-induced A549 cell death under hypoxic conditions, although hypoxia inhibited TRAIL-mediated cell apoptosis. In a mechanistic study, hypoxia inducible factor-1α and prolyl-hydroxylase 2 proteins, which increase following exposure to hypoxia, were dose-dependently down-regulated by melatonin treatment. Melatonin also blocked the hypoxic responses that reduced pro-apoptotic proteins and increased anti-apoptotic proteins including Bcl-2 and Bcl-xL. Furthermore, melatonin treatment reduced TRAIL resistance by regulating the mitochondrial transmembrane potential and Bax translocation. Our results first demonstrated that melatonin treatment induces apoptosis in TRAIL-resistant hypoxic tumor cells by diminishing the anti-apoptotic signals mediated by hypoxia and also suggest that melatonin could be a tumor therapeutic tool by combining with other apoptotic ligands including TRAIL, particularly in solid tumor cells exposed to hypoxia.http://www.mdpi.com/1422-0067/15/7/11941melatoninTRAIL (tumor necrosis factor-related apoptosis-inducing ligand)HIF-1α (hypoxia inducible factor-1α)PHD2 (prolyl-hydroxylase 2)MTP (mitochondrial transmembrane potential)Bax translocation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
You-Jin Lee Ju-Hee Lee Ji-Hong Moon Sang-Youel Park |
spellingShingle |
You-Jin Lee Ju-Hee Lee Ji-Hong Moon Sang-Youel Park Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin International Journal of Molecular Sciences melatonin TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) HIF-1α (hypoxia inducible factor-1α) PHD2 (prolyl-hydroxylase 2) MTP (mitochondrial transmembrane potential) Bax translocation |
author_facet |
You-Jin Lee Ju-Hee Lee Ji-Hong Moon Sang-Youel Park |
author_sort |
You-Jin Lee |
title |
Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin |
title_short |
Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin |
title_full |
Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin |
title_fullStr |
Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin |
title_full_unstemmed |
Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin |
title_sort |
overcoming hypoxic-resistance of tumor cells to trail-induced apoptosis through melatonin |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2014-07-01 |
description |
A solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell apoptosis under hypoxic conditions. Melatonin inhibits cell proliferation in many cancer types and induces apoptosis in some particular cancer types. Here, we examined the effects of melatonin on hypoxic resistant cells against TRAIL-induced apoptosis and the possible mechanisms of melatonin in the hypoxic response. Melatonin treatment increased TRAIL-induced A549 cell death under hypoxic conditions, although hypoxia inhibited TRAIL-mediated cell apoptosis. In a mechanistic study, hypoxia inducible factor-1α and prolyl-hydroxylase 2 proteins, which increase following exposure to hypoxia, were dose-dependently down-regulated by melatonin treatment. Melatonin also blocked the hypoxic responses that reduced pro-apoptotic proteins and increased anti-apoptotic proteins including Bcl-2 and Bcl-xL. Furthermore, melatonin treatment reduced TRAIL resistance by regulating the mitochondrial transmembrane potential and Bax translocation. Our results first demonstrated that melatonin treatment induces apoptosis in TRAIL-resistant hypoxic tumor cells by diminishing the anti-apoptotic signals mediated by hypoxia and also suggest that melatonin could be a tumor therapeutic tool by combining with other apoptotic ligands including TRAIL, particularly in solid tumor cells exposed to hypoxia. |
topic |
melatonin TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) HIF-1α (hypoxia inducible factor-1α) PHD2 (prolyl-hydroxylase 2) MTP (mitochondrial transmembrane potential) Bax translocation |
url |
http://www.mdpi.com/1422-0067/15/7/11941 |
work_keys_str_mv |
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