Oku Yusuke, Nishiya Naoyuki, Sugiyama Shuhei, Sato Haruka, Uehara Yoshimasa
Department of Integrated Information for Pharmaceutical Sciences, Iwate Medical University School of Pharmacy, Morioka, Japan
Department of Integrated Information for Pharmaceutical Sciences, Iwate Medical University School of Pharmacy, Morioka, Japan.
Anticancer Res. 2018 Jun;38(6):3471-3476. doi: 10.21873/anticanres.12617.
Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response.
YAP and TAZ were depleted using siRNA and then treated with MLN8237 in YAP/TAZ-dependent OVCAR-8 and MDA-MB-231 cell lines. MLN8237 was combined with fluvastatin, an agent constraining nuclear localisation of YAP/TAZ for potential combination therapy in vitro.
Depletion of either YAP or TAZ sensitised these cell lines to MLN8237, resulting in apoptosis and reduction in aurora-A. MLN8237 reduced YAP/TAZ expression. A combination of MLN8237 with fluvastatin effectively reduced the cell viability of OVCAR-8 and MDA-MB-231 cell lines.
A combination of MLN8237 and small-molecule agents inactivating YAP/TAZ, such as statins, could be a novel therapeutic strategy for YAP/TAZ-dependent cancer.
转录共激活因子Yes相关蛋白（YAP）和含PDZ基序的转录共激活因子（TAZ）刺激细胞周期相关基因的表达，促进肿瘤细胞生长。MLN8237是一种有效的极光激酶A抑制剂；然而，对MLN8237有反应的患者有限。因此，合理的联合治疗可以增强其疗效。
使用小干扰RNA（siRNA）使YAP和TAZ缺失，然后在依赖YAP/TAZ的卵巢癌细胞系OVCAR-8和三阴性乳腺癌细胞系MDA-MB-231中用MLN8237处理。MLN8237与氟伐他汀联合使用，氟伐他汀是一种抑制YAP/TAZ核定位的药物，用于体外潜在的联合治疗。
YAP或TAZ的缺失使这些细胞系对MLN8237敏感，导致细胞凋亡和极光激酶A减少。MLN8237降低YAP/TAZ的表达。MLN8237与氟伐他汀联合使用可有效降低OVCAR-8和MDA-MB-231细胞系的细胞活力。
MLN8237与使YAP/TAZ失活的小分子药物（如他汀类药物）联合使用，可能是治疗依赖YAP/TAZ的癌症的一种新的治疗策略。
