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Anti-angiogenic genistein inhibits VEGF-induced endothelial cell activation by decreasing PTK activity and MAPK activation

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Abstract

Genistein (Gen), a soy isoflavone, is considered to exert potent antitumor effect partially through its anti-angiogenesis property. However, the precise molecular mechanism is still unknown. Our previous investigations have demonstrated that genistein down-regulates expression of pro-angiogenic factors via inhibiting protein tyrosine kinase (PTK) activity both in breast cancer cells and in xenograft tumors. In the present experiment, we chose cultured human umbilical vein endothelial cells (HUVECs), which have a considerable role in tumor angiogenesis formation, to explore the influence of genistein on VEGF-stimulated endothelial cell activation and the underlying mechanism. Stimulation of human primary HUVECs by VEGF not only increased endothelial cell protein tyrosine kinase (PTK) activity but also augmented matrix metalloproteinase-2 (MMP-2), -9 secretions and increased MMP-2, -9 activities. Treatment of ECs with genistein induced VEGF-loaded endothelial apoptosis by inhibiting production and activity of matrix metalloproteinases (MMPs). In addition, exposure to genistein decreased activation of JNK and p38, not ERK-1/2, induced by VEGF. Collectively, our findings suggested that the inhibition of PTK activity and MAPK activation and the decrease in MMPs production and activity by genistein interrupt VEGF-stimulated endothelial cell activation, which thereby may represent a mechanism that would explain the anti-angiogenesis effect of genistein and its cancer-protective function.

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Acknowledgments

This work is supported by grants from the National Natural Science Foundation of China (30771794, 30972462), the Program for New Century Excellent Talents in University (NCET-08-0901), the Key Project of Chinese Ministry of Education (208123), Youth Technological Found of Science and Technology Department of Sichuan Province (08ZQ026-036), Emphasis Item of Education Department of Sichuan Province (07ZA015), and Found of Chengdu Medical College (CYZ07-001). We gratefully thank Yang Min MD, PhD for technical assistance and acknowledge Fred Bogott, MD, PhD (University of Minnesota, USA) for editing the textual aspects.

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Authors and Affiliations

  1. School of Public Health, Chengdu Medical College, 601# Tianhui Road, Rongdu Avenue, 610083, Chengdu, Sichuan, China

    Xiaoping Yu, Wei Chen, Qu Pan & Min Wei

  2. Department of Burn Injury and Plastic Surgery, The First Affiliated Hospital, Chengdu Medical College, 278# Baoguang Avenue, Xindu District, 610500, Chengdu, Sichuan, China

    Xiaoping Yu

  3. Department of Nutrition and Food Hygiene, School of Preventive Medicine, The Third Military Medical University, 30# Gaotanyan Street, Shapingba District, 400038, Chongqing, China

    Jundong Zhu & Mantian Mi

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  1. Xiaoping Yu
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Correspondence to Mantian Mi.

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Yu, X., Zhu, J., Mi, M. et al. Anti-angiogenic genistein inhibits VEGF-induced endothelial cell activation by decreasing PTK activity and MAPK activation. Med Oncol 29, 349–357 (2012). https://doi.org/10.1007/s12032-010-9770-2

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  • DOI: https://doi.org/10.1007/s12032-010-9770-2

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