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: Yanmin Zhang, Qian Liu, Fuwu Wang, Eng-Ang Ling, Shangming Liu, Liyan Wang, Yang Yang, Linli Yao, Xueran Chen, Fen Wang, Wei Shi, Ming Gao, Aijun Hao
• Journal: Journal of pineal research (J Pineal Res) Vol. 55 Issue 2 Pg. 121-30 (Sep 2013) ISSN: 1600-079X [Electronic] England
• PMID: 23551342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• MMP2 protein, human
• Matrix Metalloproteinase 2
• Melatonin

Topics

• Cell Line, Tumor
• Cell Movement (genetics)
• Gene Knockdown Techniques
• Glioblastoma (genetics, metabolism, pathology)
• Humans
• Hypoxia (metabolism, pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Melatonin (metabolism)
• Neoplasm Invasiveness (genetics, pathology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)