Involvement of ROS-alpha v beta 3 integrin-FAK/Pyk2 in the inhibitory effect of melatonin on U251 glioma cell migration and invasion under hypoxia
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- 作者：Cheng-Shi Xu ; Ze-Fen Wang ; Xiao-Dong Huang…
- 关键词：Melatonin ; Glioma ; Invasion ; Migration ; Hypoxia ; Focal adhesion kinase
- 刊名：Journal of Translational Medicine
- 出版年：2015
- 出版时间：December 2015
- 年：2015
- 卷：13
- 期：1
- 全文大小：1,576 KB
- 参考文献：1. Wang, J, Hao, H, Yao, L, Zhang, X, Zhao, S, Ling, EA (2012) Melatonin suppresses migration and invasion via inhibition of oxidative stress pathway in glioma cells. J Pineal Res 53: pp. 180-7 CrossRef
2. Zhang, Y, Liu, Q, Wang, F, Ling, EA, Liu, S, Wang, L (2013) Melatonin antagonizes hypoxia-mediated glioblastoma cell migration and invasion via inhibition of HIF-1alpha. J Pineal Res 55: pp. 121-30 CrossRef
3. Alvarez-Garcia, V, Gonzalez, A, Alonso-Gonzalez, C, Martinez-Campa, C, Cos, S (2013) Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J Pineal Res 54: pp. 373-80
4. Martin, V, Herrera, F, Carrera-Gonzalez, P, Garcia-Santos, G, Antolin, I, Rodriguez-Blanco, J (2006) Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 66: pp. 1081-8 CrossRef
5. Lissoni, P, Meregalli, S, Nosetto, L, Barni, S, Tancini, G, Fossati, V (1996) Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 53: pp. 43-6 CrossRef
6. Martin, V, Sanchez-Sanchez, AM, Herrera, F, Gomez-Manzano, C, Fueyo, J, Alvarez-Vega, MA (2013) Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells. Br J Cancer 108: pp. 2005-12 CrossRef
7. Reiter, RJ, Tan, DX, Mayo, JC, Sainz, RM, Leon, J, Czarnocki, Z (2003) Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 50: pp. 1129-46
8. Huang, XD, Wang, ZF, Dai, LM, Li, ZQ (2012) Microarray analysis of the hypoxia-induced gene expression profile in malignant C6 glioma cells. Asian Pac J Cancer Prev 13: pp. 4793-9 CrossRef
9. Albert, I, Hefti, M, Luginbuehl, V (2014) Physiological oxygen concentration alters glioma cell malignancy and responsiveness to photodynamic therapy in vitro. Neurol Res 36: pp. 1001-10 CrossRef
10. Hsieh, CH, Lee, CH, Liang, JA, Yu, CY, Shyu, WC (2010) Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity. Oncol Rep 24: pp. 1629-36 CrossRef
11. Li, SZ, Hu, YY, Zhao, J, Zhao, YB, Sun, JD, Yang, YF (2014) MicroRNA-34a induces apoptosis in the human glioma cell line, A172, through enhanced ROS production and NOX2 expression. Biochem Biophys Res Commun 444: pp. 6-12 CrossRef
12. Drukala, J, Urbanska, K, Wilk, A, Grabacka, M, Wybieralska, E, Valle, L (2010) ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARalpha-mediated inhibition of glioma cell motility in vitro. Mol Cancer 9: pp. 159 CrossRef
13. Zeller, KS, Riaz, A, Sarve, H, Li, J, Tengholm, A, Johansson, S (2013) The role of mechanical force and ROS in integrin-dependent signals. PLoS One 8: pp. e64897 CrossRef
14. Lin, LJ, Grimme, JM, Sun, J, Lu, S, Gai, L, Cropek, DM (2013) The antagonistic roles of PDGF and integrin alphavbeta3 in regulating ROS production at focal adhesions. Biomaterials 34: pp. 3807-15 CrossRef
15. Onishi, M, Ichikawa, T, Kurozumi, K, Date, I (2011) Angiogenesis and invasion in glioma. Brain Tumor Pathol 28: pp. 13-24 CrossRef
16. Avraham, H, Park, SY, Schinkmann, K, Avraham, S (2000) RAFTK/Pyk2-mediated cellular signalling. Cell Signal 12: pp. 1 - 刊物主题：Biomedicine general; Medicine/Public Health, general;
- 出版者：BioMed Central
- ISSN：1479-5876
文摘
Background Melatonin, a well-known antioxidant, has been shown to possess anti-invasive properties for glioma. However, little is known about the effect of melatonin on glioma cell migration and invasion under hypoxia, which is a crucial microenvironment for tumor progress. In addition, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are closely associated with cell migration and invasion. Therefore, we investigated the possible role of these kinases and its related signaling in the regulation of human U251 glioma cells behavior by melatonin under hypoxia. Methods The abilities of migration and invasion of U251 glioma cells were determined by wound healing and transwell assay in vitro. The intracellular production of reactive oxygen species (ROS) was measured by using the fluorescent probe 6-carboxy-2- 7-dichorodihydrofluorescein diacetate (DCFH-DA). Immunofluorescence experiments and western blotting analysis were used to detect the expression level of protein. Small interfering RNAs (siRNA) was used to silence specific gene expression. Results The pharmacologic concentration (1 mM) of melatonin significantly inhibited the migration and invasion of human U251 glioma cells under hypoxia. The inhibitory effect of melatonin was accompanied with the reduced phosphorylation of FAK and Pyk2, and decreased expression of alpha v beta 3 (αvβ3) integrin. Additionally, inhibition of αvβ3 integrin by siRNA reduced the phosphorylation of FAK/Pyk2 and demonstrated the similar anti-tumor effects as melatonin, suggesting the involvement of αvβ3 integrin- FAK/Pyk2 pathway in the anti-migratory and anti-invasive effect of melatonin. It was also found that melatonin treatment decreased the ROS levels in U251 glioma cells cultured under hypoxia. ROS inhibitor apocynin not only inhibited αvβ3 integrin expression and the phosphorylation levels of FAK and Pyk2, but also suppressed the migratory and invasive capacity of U251 glioma cells under hypoxia. Conclusions These results suggest that melatonin exerts anti-migratory and anti-invasive effects on glioma cells in response to hypoxia via ROS-αvβ3 integrin-FAK/Pyk2 signaling pathways. This provides evidence that melatonin may be a potential therapeutic molecule targeting the hypoxic microenvironment of glioma.