Anti-CD146 monoclonal antibody AA98 inhibits angiogenesis via suppression of nuclear factor-kappaB activation.
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 kappaB (NF-kappaB) 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-kappaB activation, and down-regulated matrix metalloproteinase 9 and intercellular adhesion molecule 1 expression, suggesting that the suppression of NF-kappaB 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.
Bu
Pengcheng
P
National Laboratory of Biomicromolecules, Institute of Biophysics, Chinese Academy of Sciences, Datun Road 15, Beijing 100101, China.
Gao
Lizeng
L
Zhuang
Jie
J
Feng
Jing
J
Yang
Dongling
D
Yan
Xiyun
X
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051929:CD146 Antigen / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051929:CD146 Antigen; D053583:Interleukin-1beta; C497902:MCAM protein, human; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9