A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition.
A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition.
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DOI：
10.1186/s12935-016-0310-9
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发表时间：
2016
影响因子：
5.8
通讯作者：
Yamada T
中科院分区：
文献类型：
--
作者：
Hayashi M;Madokoro H;Yamada K;Nishida H;Morimoto C;Sakamoto M;Yamada T
恶性间皮瘤是一种侵袭性强、预后差的肿瘤。为了有效地治疗多发性骨髓瘤，迫切需要多模式治疗和新型分子靶向治疗。我们开发了一种人源化单克隆抗体YS110，抗CD26，在85%的MM病例中表达。CD26被认为通过与胶原蛋白和纤维连接蛋白相互作用或影响信号转导过程参与肿瘤的生长和侵袭。我们评价了YS110对MM细胞株、NCI-H2452和JMN的直接抗肿瘤作用，并研究了其对细胞周期和细胞周期调节分子的影响。此外，我们还在体外和体内研究了YS110和抗肿瘤药物培美曲塞（pemetrexed， PMX）对MM细胞系的协同作用。在48 h内，YS110对NCI-H2452细胞的增殖抑制作用约为20%。细胞周期分析显示，YS110处理后，G2/M期细胞比例平均增加8.0%；此外，YS110处理后细胞周期调节因子p21 cip/waf1升高，细胞周期蛋白B1降低。cdc2 （Tyr15）和cdc25C （Ser216）的抑制性磷酸化均升高。此外，在YS110处理24小时后，p38 MAPK （Thr180/Tyr182）和ERK1/2 （Thr202/Tyr204）的活化磷酸化增强。PMX快速诱导CD26在细胞表面的表达，YS110和PMX治疗抑制体内肿瘤生长，同时协同降低mb -1指数。本文首次报道了人源化抗cd26单克隆抗体YS110通过调节各种细胞周期调节分子的数量和活性导致G2/M细胞周期延迟的新抗增殖机制。
Malignant Mesothelioma (MM) is a highly aggressive tumor with poor prognosis. Multimodal treatments and novel molecular targeted therapies against MM are in high demand in order treat this disease effectively. We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases. CD26 is thought to be involved in tumor growth and invasion by interacting with collagen and fibronectin, or affecting signal transduction processes. We evaluated the direct anti-tumor effect of YS110 against MM cell lines, NCI-H2452 and JMN, and investigated its effects on cell cycle and on the cell cycle regulator molecules. In addition, we investigated synergistic effects of YS110 and anti-tumor agent pemetrexed (PMX) against MM cell line both in vitro and in vivo. YS110 suppressed the proliferation of NCI-H2452 cells by approximately 20 % in 48 h. Based on cell cycle analysis, percentage of cells in G2/M phase increased 8.0 % on the average after YS110 treatment; in addition, cell cycle regulator p21 cip/waf1 was increased and cyclin B1 was decreased after YS110 treatment. Inhibitory phosphorylation of both cdc2 (Tyr15) and cdc25C (Ser216) were elevated. Furthermore, activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were augmented at 24 h after YS110 treatment. PMX rapidly induced CD26 expression on cell surface and the treatment with both YS110 and PMX inhibited in vivo tumor growth accompanied by a synergistic reduction in the MIB-1 index. This is a first report of a novel anti-proliferative mechanism of the humanized anti-CD26 monoclonal antibody YS110, which resulted in G2/M cell cycle delay through regulation of quantity and activity of various cell cycle regulating molecules.