JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer
JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer
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DOI：
10.1016/j.ejca.2019.11.017
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发表时间：
2020-02-01
影响因子：
8.4
通讯作者：
Bamias, Aristotle
中科院分区：
文献类型：
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作者：
Bagratuni, Tina;Mavrianou, Nefeli;Bamias, Aristotle
背景：c-Myc 过度表达常见于人类卵巢癌，这可能成为该疾病的潜在新治疗靶点。 JQ1 是一种选择性小分子 BET（布罗莫结构域和末端结构域家族）布罗莫结构域 (BRD) 抑制剂，已被发现能够抑制多种癌细胞类型的肿瘤进展。结果：使用一组卵巢癌细胞系和来自人卵巢癌腹水的原代细胞培养物，我们证明 JQ1 通过靶向作用显着抑制卵巢癌细胞的细胞增殖并诱导细胞凋亡 BRD4 和 c-Myc。此外，JQ1 使卵巢癌细胞对顺铂（卵巢癌最常用的化疗药物）敏感。重要的是，这种效应在卵巢细胞中观察到，这些细胞对单独的顺铂表现出耐药性。最后，我们证明 JQ1 与 JAK-STAT 信号通路相互作用，JAK-STAT 信号通路是通过分别抑制或诱导参与细胞存活和凋亡的基因来支持卵巢癌细胞存活的重要通路。结论：我们的数据综合起来表明，JQ1 是一种有吸引力的抗肿瘤候选药物，可用于进一步研究卵巢癌的治疗，因为它与细胞增殖、凋亡和细胞凋亡的改变相关。 JAK-STAT 信号通路，尤其是在铂类耐药的患者或疾病复发的患者中。 (C) 2019 Elsevier Ltd. 保留所有权利。
Background: Overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET (Bromodomain and extraterminal domain family) bromodomain (BRDs) inhibitor, has been found to suppress tumour progression in several cancer cell types.Results: Using a panel of ovarian cancer cell lines and primary cell cultures from human ovarian cancer ascites, we demonstrated that JQ1 significantly suppressed cell proliferation and induced apoptosis in an ovarian cancer cell by targeting BRD4 and c-Myc. In addition, JQ1 sensitized ovarian cancer cells to cisplatin, the most commonly used chemotherapeutic agent in ovarian cancer. Importantly, this effect was observed in ovarian cells, which exhibited resistance to cisplatin alone. Finally, we show that JQ1 interacts with the JAK-STAT signalling pathway, a pathway important in supporting ovarian cancer cell survival by suppressing or inducing genes involved in cell survival and apoptosis, respectively.Conclusion: Our data, taken together, suggest that JQ1 is an attractive antitumour candidate for further investigation in the treatment of ovarian cancer, as it associates with cell proliferation, apoptosis, and alterations in the JAK-STAT signalling pathway, especially in patients with a platinum-resistant profile or in patients with relapsed disease. (C) 2019 Elsevier Ltd. All rights reserved.