Yongxia Zhu1, Zhihao Liu2, Yanling Qu2, Jun Zeng2, Meiqin Yang1, Xiaoyi Li1, Zhaodi Wang1, Junxiang Su3, Xueqin Wang1, Luoting Yu4, Yue Wang5. 1. Department of Obstetrics and Gynecology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No. 7 Weiwu Road, Zhengzhou, 450003, Henan, China. 2. State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China. 3. Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China. 4. State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China. yuluot@scu.edu.cn. 5. Department of Obstetrics and Gynecology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No. 7 Weiwu Road, Zhengzhou, 450003, Henan, China. wangyue0601@163.com.
Abstract
PURPOSE: Polo-like kinase 4 (PLK4), a member of the polo-like kinase family, plays several important roles in mitotic regulation, including centrosome duplication, spindle formation, and cytokinesis. PLK4 overexpression is frequently detected in many human cancers, including ovarian cancer, and the inhibition of PLK4 activity results in cancer cell mitotic arrest and apoptosis. Therefore, PLK4 might be a valid therapeutic target for antitumor therapy. In the present study, we aimed to determine if YLZ-F5, a potent small-molecule inhibitor of PLK4, inhibits ovarian cancer cell growth. METHODS AND RESULTS: MTT assay showed that YLZ-F5 inhibited ovarian cancer cell proliferation in a concentration- and time-dependent manner. The results of colony formation assays were consistent with those of the MTT assay results. In addition, YLZ-F5 induced ovarian cancer cell apoptosis that was associated with activation of caspase-3/caspase-9. Moreover, YLZ-F5 caused aberrant in centriole duplication that was associated with the inhibition of PLK4 phosphorylation. Notably, we showed that YLZ-F5 promoted the accumulation of ovarian cancer cells with mitotic defects (> 4 N DNA content) in a concentration-dependent manner. Furthermore, YLZ-F5 markedly inhibited the migration of A2780 cells. CONCLUSION: Taken together, these findings suggest that YLZ-F5 is a potential drug candidate for human ovarian cancer.
PURPOSE: Polo-like kinase 4 (PLK4), a member of the polo-like kinase family, plays several important roles in mitotic regulation, including centrosome duplication, spindle formation, and cytokinesis. PLK4 overexpression is frequently detected in many human cancers, including ovarian cancer, and the inhibition of PLK4 activity results in cancer cell mitotic arrest and apoptosis. Therefore, PLK4 might be a valid therapeutic target for antitumor therapy. In the present study, we aimed to determine if YLZ-F5, a potent small-molecule inhibitor of PLK4, inhibits ovarian cancer cell growth. METHODS AND RESULTS: MTT assay showed that YLZ-F5 inhibited ovarian cancer cell proliferation in a concentration- and time-dependent manner. The results of colony formation assays were consistent with those of the MTT assay results. In addition, YLZ-F5 induced ovarian cancer cell apoptosis that was associated with activation of caspase-3/caspase-9. Moreover, YLZ-F5 caused aberrant in centriole duplication that was associated with the inhibition of PLK4 phosphorylation. Notably, we showed that YLZ-F5 promoted the accumulation of ovarian cancer cells with mitotic defects (> 4 N DNA content) in a concentration-dependent manner. Furthermore, YLZ-F5 markedly inhibited the migration of A2780 cells. CONCLUSION: Taken together, these findings suggest that YLZ-F5 is a potential drug candidate for human ovarian cancer.
Authors: Rosemary D Cress; Yingjia S Chen; Cyllene R Morris; Megan Petersen; Gary S Leiserowitz Journal: Obstet Gynecol Date: 2015-09 Impact factor: 7.661