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Melatonin antagonizes hypoxia‐mediated glioblastoma cell migration and invasion via inhibition of HIF ‐1α
Author(s) -
Zhang Yanmin,
Liu Qian,
Wang Fuwu,
Ling EngAng,
Liu Shangming,
Wang Liyan,
Yang Yang,
Yao Linli,
Chen Xueran,
Wang Fen,
Shi Wei,
Gao Ming,
Hao Aijun
Publication year - 2013
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12052
Subject(s) - melatonin , hypoxia (environmental) , gene silencing , small interfering rna , cancer research , matrix metalloproteinase , vascular endothelial growth factor , biology , cell migration , angiogenesis , cell , endocrinology , medicine , cell culture , chemistry , transfection , vegf receptors , gene , biochemistry , oxygen , genetics , organic chemistry
Hypoxia is a crucial factor in tumor aggressiveness and resistance to therapy, especially in glioblastoma. Our previous results have shown that melatonin exerts antimigratory and anti‐invasive action in glioblastoma cells under normoxia. However, the effect of melatonin on migration and invasion of glioblastoma cells under hypoxic condition remains poorly understood. Here, we show that melatonin strongly reduced hypoxia‐mediated invasion and migration of U 251 and U 87 glioblastoma cells. In addition, we found that melatonin significantly blocked HIF ‐1α protein expression and suppressed the expression of downstream target genes, matrix metalloproteinase 2 ( MMP ‐2) and vascular endothelial growth factor ( VEGF ). Furthermore, melatonin destabilized hypoxia‐induced HIF ‐1α protein via its antioxidant activity against ROS produced by glioblastoma cells in response to hypoxia. Along with this, HIF ‐1α silencing by small interfering RNA markedly inhibited glioblastoma cell migration and invasion, and this appeared to be associated with MMP ‐2 and VEGF under hypoxia. Taken together, our findings suggest that melatonin suppresses hypoxia‐induced glioblastoma cell migration and invasion via inhibition of HIF ‐1α. Considering the fact that overexpression of the HIF ‐1α protein is often detected in glioblastoma multiforme, melatonin may prove to be a potent therapeutic agent for this tumor.