Wang Lixia, Hou Yingying, Yin Xuyuan, Su Jingna, Zhao Zhe, Ye Xiantao, Zhou Xiuxia, Zhou Li, Wang Zhiwei
The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, China.
Department of Gynecologic Oncosurgery, Jilin province Cancer Hospital, Changchun, Jilin, China.
Oncotarget. 2016 Oct 25;7(43):69770-69782. doi: 10.18632/oncotarget.11974.
Rottlerin, isolated from a medicinal plant Mallotus phillippinensis, has been demonstrated to inhibit cellular growth and induce cytoxicity in glioblastoma cell lines through inhibition of calmodulin-dependent protein kinase III. Emerging evidence suggests that rottlerin exerts its antitumor activity as a protein kinase C inhibitor. Although further studies revealed that rottlerin regulated multiple signaling pathways to suppress tumor cell growth, the exact molecular insight on rottlerin-mediated tumor inhibition is not fully elucidated. In the current study, we determine the function of rottlerin on glioma cell growth, apoptosis, cell cycle, migration and invasion. We found that rottlerin inhibited cell growth, migration, invasion, but induced apoptosis and cell cycle arrest. Mechanistically, the expression of Cdc20 oncoprotein was measured by the RT-PCR and Western blot analysis in glioma cells treated with rottlerin. We observed that rottlerin significantly inhibited the expression of Cdc20 in glioma cells, implying that Cdc20 could be a novel target of rottlerin. In line with this, over-expression of Cdc20 decreased rottlerin-induced cell growth inhibition and apoptosis, whereas down-regulation of Cdc20 by its shRNA promotes rottlerin-induced anti-tumor activity. Our findings indicted that rottlerin could exert its tumor suppressive function by inhibiting Cdc20 pathway which is constitutively active in glioma cells. Therefore, down-regulation of Cdc20 by rottlerin could be a promising therapeutic strategy for the treatment of glioma.
从药用植物菲律宾叶下珠中分离出的rottlerin，已被证明可通过抑制钙调蛋白依赖性蛋白激酶III来抑制胶质母细胞瘤细胞系中的细胞生长并诱导细胞毒性。新出现的证据表明，rottlerin作为一种蛋白激酶C抑制剂发挥其抗肿瘤活性。尽管进一步的研究表明rottlerin调节多种信号通路以抑制肿瘤细胞生长，但对rottlerin介导的肿瘤抑制的确切分子机制尚未完全阐明。在本研究中，我们确定了rottlerin对胶质瘤细胞生长、凋亡、细胞周期、迁移和侵袭的作用。我们发现rottlerin抑制细胞生长、迁移和侵袭，但诱导凋亡和细胞周期停滞。机制上，在用rottlerin处理的胶质瘤细胞中，通过RT-PCR和蛋白质印迹分析检测细胞分裂周期蛋白20（Cdc20）癌蛋白的表达。我们观察到rottlerin显著抑制胶质瘤细胞中Cdc20的表达，这意味着Cdc20可能是rottlerin的一个新靶点。与此一致，Cdc20的过表达降低了rottlerin诱导的细胞生长抑制和凋亡，而通过其短发夹RNA下调Cdc20则促进了rottlerin诱导的抗肿瘤活性。我们的研究结果表明，rottlerin可通过抑制在胶质瘤细胞中组成性激活的Cdc20途径发挥其肿瘤抑制功能。因此，rottlerin下调Cdc20可能是一种有前景的治疗胶质瘤的策略。
