Qiu Haifeng, Li Jing, Clark Leslie H, Jackson Amanda L, Zhang Lu, Guo Hui, Kilgore Joshua E, Gehrig Paola A, Zhou Chunxiao, Bae-Jump Victoria L
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Oncotarget. 2016 Oct 11;7(41):66809-66821. doi: 10.18632/oncotarget.11631.
Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers.
c-Myc的过表达与子宫内膜癌的不良预后相关，这表明c-Myc可能是子宫内膜癌治疗的一个有前景的靶点。一种新型小分子JQ1已被证明可阻断BRD4，从而抑制c-Myc表达和肿瘤生长。因此，我们研究了JQ1在细胞培养和异种移植模型中是否能抑制子宫内膜癌的生长。在PTEN阳性的子宫内膜癌细胞中，JQ1通过诱导G1期阻滞和凋亡以剂量依赖的方式显著抑制细胞增殖，同时细胞周期蛋白D1和CDK4蛋白表达急剧下降。然而，PTEN阴性的子宫内膜癌细胞尽管c-Myc受到显著抑制，但对JQ1表现出内在抗性。此外，我们发现JQ1可调节PTEN及其下游的PI3K/AKT信号靶点，这在微阵列分析中得到了证实。在PTEN阳性的子宫内膜癌细胞中沉默PTEN会导致对JQ1产生抗性，而在PTEN阴性的子宫内膜癌细胞中上调PTEN则会增加对JQ1的敏感性。在PTEN阳性和PTEN敲入的子宫内膜癌异种移植模型中，JQ1显著上调PTEN的表达，阻断PI3K/AKT信号通路并抑制肿瘤生长。在PTEN阴性和PTEN敲低的异种移植模型中，这些作用减弱。因此，JQ1抗性似乎与子宫内膜癌中PTEN的表达状态高度相关。我们的研究结果表明，使用JQ1靶向BRD4可能是PTEN阳性子宫内膜癌的一种新型治疗策略。
