Wu Chao-Chih, Weng Chia-Sui, Hsu Yun-Ting, Chang Chih-Long
Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan.
Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan.
Taiwan J Obstet Gynecol. 2019 Jan;58(1):145-152. doi: 10.1016/j.tjog.2018.11.027.
Tyrosine-protein kinase MET (c-MET) has been reported to be a prognostic marker and suitable therapeutic target for ovarian cancer. BMS-777607, a small molecule, can inhibit MET and other protein kinase activities. The present study was conducted to investigate the mechanism of action and antitumor effect of BMS-777607 on ovarian cancer cells with constitutively activated c-MET.
Ovarian cancer cells with constitutively activated c-MET were first identified through Western blot analysis. Bio-behaviors, including signal transduction, proliferation, apoptosis, and migration, of the cells with constitutively activated c-MET were evaluated after BMS-777607 treatment. Liu's stain and immunological staining of α-tubuline were performed to evaluate the ploidy of the cells. A xenograft mouse model was also used to evaluate the antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET.
BMS-777607 could induce the highest inhibition of cell growth in ovarian cancer cells constitutively expressing c-MET. Treating SKOV3 cells with BMS-777607 could reduce c-MET activation and inhibit downstream cell signaling, thus causing cell apoptosis and polyploidy as well as cell cycle and cell migration inhibition. This molecule also inhibited tumor growth in a mouse xenograft model of SKOV3 ovarian cancer cells in vivo.
BMS-777607 exhibits antitumor effects on ovarian cancer cells that constitutively express c-MET through c-MET signaling blockade and the inhibition of Aurora B activity. Combination treatments to enhance the effects of BMS-777607 warrant investigation in the future.
酪氨酸蛋白激酶MET（c-MET）已被报道为卵巢癌的预后标志物和合适的治疗靶点。小分子BMS-777607可抑制MET及其他蛋白激酶活性。本研究旨在探讨BMS-777607对组成性激活c-MET的卵巢癌细胞的作用机制和抗肿瘤效果。
首先通过蛋白质印迹分析鉴定组成性激活c-MET的卵巢癌细胞。在BMS-777607处理后，评估组成性激活c-MET的细胞的生物行为，包括信号转导、增殖、凋亡和迁移。进行刘氏染色和α-微管蛋白免疫染色以评估细胞的倍性。还使用异种移植小鼠模型评估BMS-777607对组成性激活c-MET的卵巢癌细胞的抗肿瘤作用。
BMS-777607可诱导组成性表达c-MET的卵巢癌细胞中细胞生长的最高抑制。用BMS-777607处理SKOV3细胞可降低c-MET激活并抑制下游细胞信号传导，从而导致细胞凋亡和多倍体形成以及细胞周期和细胞迁移抑制。该分子在体内SKOV3卵巢癌细胞的小鼠异种移植模型中也抑制肿瘤生长。
BMS-777607通过c-MET信号传导阻断和抑制Aurora B活性对组成性表达c-MET的卵巢癌细胞表现出抗肿瘤作用。未来需要研究联合治疗以增强BMS-777607的效果。
