This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bu, P. Articles by Yan, X. Search for Related Content PubMed PubMed Citation Articles by Bu, P. Articles by Yan, X.

Research Articles: Therapeutics, Targets, and Development

Anti-CD146 monoclonal antibody AA98 inhibits angiogenesis via suppression of nuclear factor-B activation

¹ National Laboratory of Biomicromolecules, Institute of Biophysics, and ² Graduate School, Chinese Academy of Sciences, Beijing, China

Requests for reprints: Xiyun Yan, National Laboratory of Biomicromolecules, Institute of Biophysics, Chinese Academy of Sciences, Datun Road 15, Beijing 100101, China. Phone: 86-10-6488-8583; Fax: 86-10-6488-8584. E-mail: yanxy{at}sun5.ibp.ac.cn

Abstract

Our previous study showed that an anti-CD146 monoclonal antibody (mAb), AA98, which was raised against the vascular endothelial cells stimulated by a conditioned medium from hepatocarcinoma SMMC 7721 cells (SMMC 7721-CM), inhibited cell migration, angiogenesis, and tumor growth. However, the underlying mechanism was not elucidated. The objective of this study was to understand the mechanism by which mAb AA98 inhibits the endothelial cell migration and angiogenesis that is induced by SMMC 7721-CM. Using confocal imaging and biochemical studies, we found that SMMC 7721-CM induced nuclear factor B (NF-B) activation through the upstream p38 mitogen-activated protein kinase pathway, leading to the up-regulation of matrix metalloproteinase 9 and intercellular adhesion molecule 1 expression. Interestingly, all these activities stimulated by SMMC 7721-CM could be effectively inhibited by mAb AA98 in a dose- and time-dependent manner. Our data showed that the engagement of mAb AA98 with membrane protein CD146 inhibited p38 mitogen-activated protein kinase phosphorylation, suppressed NF-B activation, and down-regulated matrix metalloproteinase 9 and intercellular adhesion molecule 1 expression, suggesting that the suppression of NF-B is a critical point for the inhibitory function of mAb AA98 on endothelial cell migration, angiogenesis, and tumor metastasis. These results will provide clues for a better understanding of the mechanisms underlying tumor angiogenesis as well as antiangiogenesis therapy. [Mol Cancer Ther 2006;5(11):2872–8]

Grant support: Partial grants from the National Natural Sciences Foundation of China, National 863, and the Chinese Academy of Sciences.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/ 8/06; revised 7/20/06; accepted 9/20/06.