文章：

Silmitasertib (CX-4945) 通过破坏CK2β功能，瓦解ERα/HSP90相互作用并驱动乳腺癌细胞中的蛋白降解

Silmitasertib (CX-4945) Disrupts ERα/HSP90 Interaction and Drives Proteolysis through the Disruption of CK2β Function in Breast Cancer Cells

原文发布日期：10 July 2024

DOI: 10.3390/cancers16142501

类型: Article

开放获取: 是

英文摘要：

Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. ERα36, an alternative isoform of ERα, contributes to these effects. We have demonstrated that CK2 modulates ERα expression and function in breast cancer (BCa). Here, we assess if CX-4945 (CX), a clinical stage CK2 inhibitor, can disrupt ERα66 and ERα36 signaling in BCa. Using live cell imaging, we assessed the antiproliferative effects of CX in tamoxifen-sensitive and tamoxifen-resistant BCa cells in monolayer and/or spheroid cultures. CX-induced alterations in ERα66 and ERα36 mRNA and protein expression were assessed by RT-PCR and immunoblot. Co-immunoprecipitation was performed to determine the differential interaction of ERα isoforms with HSP90 and CK2 upon CX exposure. CX caused concentration-dependent decreases in proliferation in tamoxifen-sensitive MCF-7 and tamoxifen-resistant MCF-7 Tam1 cells and significantly repressed spheroid growth in 3D models. Additionally, CX caused dramatic decreases in endogenous or exogenously expressed ERα66 and ERα36 protein. Silencing of CK2β, the regulatory subunit of CK2, resulted in destabilization and decreased proliferation, similar to CX. Co-immunoprecipitation demonstrated that ERα66/36 show CK2 dependance for interaction with molecular chaperone HSP90. Our findings show that CK2 functions regulate the protein stability of ERα66 and ERα36 through a mechanism that is dependent on CK2β subunit and HSP90 chaperone function. CX may be a component of a novel therapeutic strategy that targets both tamoxifen-sensitive and tamoxifen-resistant BCa, providing an additional tool to treat ERα-positive BCa.

摘要翻译： 

异常雌激素受体（ERα）信号通路介导了他莫昔芬的有害效应，包括耐药性和子宫内膜增生。ERα36作为ERα的一种亚型，参与了这些效应的发生。我们先前已证实CK2在乳腺癌中调控ERα的表达与功能。本研究旨在评估临床阶段CK2抑制剂CX-4945（CX）能否阻断乳腺癌中ERα66和ERα36的信号传导。通过活细胞成像技术，我们在单层和/或球体培养模型中评估了CX对他莫昔芬敏感型及耐药型乳腺癌细胞的抗增殖作用。采用RT-PCR和免疫印迹法检测CX对ERα66和ERα36 mRNA及蛋白表达的影响。通过免疫共沉淀实验分析CX作用下ERα亚型与HSP90及CK2相互作用的差异。实验结果显示，CX能浓度依赖性地抑制他莫昔芬敏感型MCF-7细胞及耐药型MCF-7 Tam1细胞的增殖，并在三维模型中显著抑制球体生长。此外，CX可显著降低内源性或外源性表达的ERα66和ERα36蛋白水平。沉默CK2调节亚基CK2β可产生与CX类似的效果，导致蛋白稳定性下降及细胞增殖抑制。免疫共沉淀实验表明ERα66/36与分子伴侣HSP90的相互作用具有CK2依赖性。我们的研究结果表明，CK2通过依赖CK2β亚基和HSP90伴侣功能的机制调控ERα66和ERα36的蛋白稳定性。CX可能成为靶向他莫昔芬敏感型与耐药型乳腺癌的新型治疗策略的重要组成部分，为ERα阳性乳腺癌的治疗提供新工具。

原文链接：

Silmitasertib (CX-4945) Disrupts ERα/HSP90 Interaction and Drives Proteolysis through the Disruption of CK2β Function in Breast Cancer Cells