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Sp1 inhibition-mediated upregulation of VEGF165b induced by rh-endostatin enhances antiangiogenic and anticancer effect of rh-endostatin in A549

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Tumor Biology

Abstract

Recombinant human endostatin (rh-endostatin), a potential antiangiogenic agent, is used in non-small cell lung carcinoma treatment and represses vascular endothelial cell growth factor (VEGF) levels in tumor cell. However, precise affection of rh-endostatin on the proangiogenic VEGF isoforms (VEGF165) or antiangiogenic VEGF isoforms (VEGF165b) is not clear. We therefore tested the hypothesis that rh-endostatin could alter expression of these isoforms to regulate tumor growth. A549 cells were exposed to rh-endostatin, and the expression of VEGF165 and VEGF165b was detected. The role of SP1 as a regulator of isoform expression was investigated. We then examined the anticancer and antiangiogenic efficacy of rh-endostatin in combination with exogenous VEGF165b against A549 cells, EA.HY 926 cells and xenograft model of human lung cancer. rh-Endostatin reduced VEGF165 and induced VEGF165b as well as inhibited SP1 in A549 cells. SP1 inhibitor (betulinic acid) also developed those changes. VEGF165b–rh-endostatin combination was highly synergistic and inhibited growth, survival, and migration of A549 cells, VEGF-mediated VEGFR2 phosphorylation in EA.HY 926 cells, and tumor growth in xenograft model of human lung cancer. rh-Endostatin downregulates proangiogenic vascular endothelial growth factor A (VEGFA) isoform and upregulates antiangiogenic VEGFA isoform, possibly through inhibition of SP1. Furthermore, VEGF165b sensitizes A549 to rh-endostatin treatment and enhances the anticancer effect of rh-endostatin.

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Acknowledgments

This study was financially supported by the key program of the Natural Science Foundation of Hubei Province (no. 2009CDA061) and Simcere Pharmaceutical Research Co., Ltd., Jiangsu Province, P.R.China.

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Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People’s Republic of China

    Zhen-yu Li, Fang Zhu, Jian-li Hu, Gang Peng, Jing Chen, Sheng Zhang, Rui-guang Zhang, Ling-juan Chen, Pian Liu, Ming Luo, Zhi-hua Sun, Jing-hua Ren, Li-li Huang & Gang Wu

  2. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei Province, People’s Republic of China

    Xu Chen

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  1. Zhen-yu Li
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Correspondence to Gang Wu.

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Li, Zy., Zhu, F., Hu, Jl. et al. Sp1 inhibition-mediated upregulation of VEGF165b induced by rh-endostatin enhances antiangiogenic and anticancer effect of rh-endostatin in A549. Tumor Biol. 32, 677–687 (2011). https://doi.org/10.1007/s13277-011-0168-3

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  • DOI: https://doi.org/10.1007/s13277-011-0168-3

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