Obstetrics and Gynecology Department, People's Hospital of Zoucheng, Jining, Shandong, China.
Obstetrics and Gynecology Department, Affiliated Hospital of Jining Medical College, 89 Guhuai Rd, Jining, 272000, Shandong, China.
Cell Tissue Res. 2018 Dec;374(3):577-585. doi: 10.1007/s00441-018-2906-y. Epub 2018 Sep 4.
Ovarian cancer (OC) is a common malignant tumor with a high probability of metastasis. Thus, it is urgently necessary to develop new drugs that inhibit tumor metastasis. Bromodomain and extraterminal (BET) inhibitors targeting bromodomain-containing proteins are currently recognized as novel anticancer agents. Herein, we explored the effects of i-BET151, a BET bromodomain inhibitor, on OC metastasis and on antitumor immunity. Our experiments showed that i-BET151 decreased the viability and induced apoptosis, senescence, and cell cycle arrest of cancer cells. In addition, phosphorylated-Stat3 (Tyr705) amounts OC cell invasion and migration, and expression of matrix metalloproteinases (MMP-9 and MMP-2) decreased. Moreover, tumor metastasis in the abdomen of the OC model was inhibited by i-BET151. Notably, i-BET151-promoted immunogenic cell death (ICD) was confirmed in vivo; it was demonstrated with ICD markers. Furthermore, treatment with i-BET151 promoted infiltration by CD8 T cells as well as the death of immunogenic tumor cells. In summary, tumor metastasis may be suppressed by i-BET151 via the Stat3 pathway; this approach could be used as a strategy for the treatment of OC.
卵巢癌(OC)是一种常见的恶性肿瘤,具有较高的转移概率。因此,迫切需要开发抑制肿瘤转移的新药。靶向含溴结构域蛋白的溴结构域和末端(BET)抑制剂目前被认为是新型抗癌药物。在此,我们探讨了 BET 溴结构域抑制剂 i-BET151 对 OC 转移和抗肿瘤免疫的影响。我们的实验表明,i-BET151 降低了癌细胞的活力,并诱导其凋亡、衰老和细胞周期停滞。此外,磷酸化 Stat3(Tyr705)促进了 OC 细胞的侵袭和迁移,基质金属蛋白酶(MMP-9 和 MMP-2)的表达减少。此外,i-BET151 抑制了 OC 模型腹部的肿瘤转移。值得注意的是,体内实验证实了 i-BET151 促进免疫原性细胞死亡(ICD);通过 ICD 标志物得到了证实。此外,i-BET151 的治疗促进了 CD8 T 细胞的浸润和免疫原性肿瘤细胞的死亡。总之,i-BET151 可能通过 Stat3 通路抑制肿瘤转移,这一方法可用作 OC 的治疗策略。