Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway
Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway
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DOI：
10.1080/21691401.2019.1670670
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发表时间：
2019-12-04
影响因子：
5.8
通讯作者：
Zhou, Yunfeng
中科院分区：
文献类型：
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作者：
Li, Tianqi;Xiong, Yudi;Zhou, Yunfeng
三阴性乳腺癌（TNBC）是一种难治性亚型，预测预后较差，目前尚无有效的治疗方法来改善它。鉴于传统治疗方法的局限性，需要挖掘新的治疗策略来减轻内在或获得性耐药性。Ribociclib是一种选择性CDK4/6抑制剂，通过干预CDK4/6-cyclin D-Rb-E2F通路，成功地阻止了癌症的恶化，特别是对于雌激素受体阳性（ER +）乳腺癌。然而，参考TNBC，可访问性仍然有限。通过对MDA-MB-231细胞的实验，我们发现LEE011可以抑制细胞增殖，并且这种抑制倾向于剂量依赖性。Western blotting分析显示，LEE011处理后CDK4/6表达显著降低，与该轴相关的其他蛋白如cyclin D1、p-Rb、Rb、E2F1出现异常变化。LEE011诱导G(0)？G(1)期细胞周期阻滞，促进细胞凋亡，减少细胞迁移。此外，MDA-MB-231异种移植模型的肿瘤生长明显受阻，无明显副作用。我们的研究已经确定LEE011对MDA-MB-231并不完全无效。考虑到其在TNBC中的关键地位，CDK4/6-cyclin D-Rb-E2F通路告诉我们Ribociclib （LEE011）作为药物干预的可能性和实用性，但挑战需要在前瞻性研究中进一步验证。
Triple-negative breast cancer (TNBC) stands for a refractory subtype, which predicts poor prognosis and has no effective therapies yet for improving it. Given the restrictions of traditional treatments, novel therapeutic strategies need excavating to alleviate the intrinsic or acquired resistance. Ribociclib, a selective CDK4/6 inhibitor, has successfully prevented cancers from deteriorating by intervening the CDK4/6-cyclin D-Rb-E2F pathway, especially for estrogen receptor-positive (ER +) breast cancer. However, there still remains limited accessibility referring to TNBC. Performing experiments on MDA-MB-231 cells, we found that LEE011 could suppress cell proliferation, and this suppression tended to be dose-dependently. Western blotting analysis presented significant decrease with the expression of CDK4/6 after LEE011 treated, and other proteins associated with this axis such as cyclin D1, p-Rb, Rb, E2F1 showed aberrant changes. Moreover, LEE011 induced G(0)?G(1) phase cell cycle arrest, promoted cell apoptosis, and reduced cell migration in vitro. In addition, tumor growth was remarkably impeded without obvious side-effects in MDA-MB-231 xenograft models. Our research has identified that LEE011 was not completely invalid for MDA-MB-231. Considering its pivotal status in TNBC, the CDK4/6-cyclin D-Rb-E2F pathway informed us the possibility and practicality of Ribociclib (LEE011) as pharmacological intervention, but challenges warrant further validation in prospective studies.