title: Melatonin antagonizes hypoxia-mediated glioblastoma cell migration and invasion via inhibition of HIF-1α.
abstract: 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 U251 and U87 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.
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, Jinan, China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Fuwu
authors.initials: F
authors.lastname: Wang
authors.forename: Eng-Ang
authors.initials: EA
authors.lastname: Ling
authors.forename: Shangming
authors.initials: S
authors.lastname: Liu
authors.forename: Liyan
authors.initials: L
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Linli
authors.initials: L
authors.lastname: Yao
authors.forename: Xueran
authors.initials: X
authors.lastname: Chen
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Aijun
authors.initials: A
authors.lastname: Hao
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D008550:Melatonin
keywords: HIF-1α; glioblastoma multiforme; hypoxia; invasion; melatonin; migration