文章：

α-连接蛋白羧基末端肽（aCT1）在耐药性HER2阳性乳腺癌中抗癌活性的作用机制研究

Mapping the Anti-Cancer Activity of α-Connexin Carboxyl-Terminal (aCT1) Peptide in Resistant HER2+ Breast Cancer

原文发布日期：19 January 2024

DOI: 10.3390/cancers16020423

类型: Article

开放获取: 是

英文摘要：

Connexin 43 (Cx43) is a protein encoded by theGJA1gene and is a component of cell membrane structures called gap junctions, which facilitate intercellular communication. Prior evidence indicates that elevatedGJA1expression in the HER2-positive (HER2+) subtype of breast cancer is associated with poor prognosis. Prior evidence also suggests that HER2+ breast cancers that have become refractory to HER2-targeted agents have a loss of Cx43 gap junction intercellular communication (GJIC). In this study, a Cx43-targeted agent called alpha-connexin carboxyl-terminal peptide (aCT1) is examined to determine whether GJIC can be rescued in refractory HER2+ breast cancer cells. A proposed mechanism of action for aCT1 is binding to the tight junction protein Zonal Occludens-1 (ZO-1). However, the true scope of activity for aCT1 has not been explored. In this study, mass spectrometry proteomic analysis is used to determine the breadth of aCT1-interacting proteins. The NanoString nCounter Breast Cancer 360 panel is also used to examine the effect of aCT1 on cancer signaling in HER2+ breast cancer cells. Findings from this study show a dynamic range of binding partners for aCT1, many of which regulate gene expression and RNA biology. nCounter analysis shows that a number of pathways are significantly impacted by aCT1, including upregulation of apoptotic factors, leading to the prediction and demonstration that aCT1 can boost the cell death effects of cisplatin and lapatinib in HER2+ breast cancer cells that have become resistant to HER2-targeted agents.

摘要翻译： 

连接蛋白43（Cx43）是由GJA1基因编码的蛋白质，是构成细胞间隙连接的重要组分，介导细胞间通讯。已有证据表明，在HER2阳性（HER2+）亚型乳腺癌中，GJA1表达升高与不良预后相关。研究还发现，对HER2靶向药物产生耐药的HER2+乳腺癌会丧失Cx43介导的间隙连接细胞通讯（GJIC）功能。本研究通过一种靶向Cx43的制剂——α-连接蛋白羧基末端肽（aCT1），探究其能否在耐药性HER2+乳腺癌细胞中恢复GJIC功能。aCT1的作用机制被认为是通过结合紧密连接蛋白ZO-1实现，但其确切作用范围尚未明确。本研究采用质谱蛋白质组学分析技术系统鉴定aCT1的相互作用蛋白谱，并运用NanoString nCounter乳腺癌360基因检测面板分析aCT1对HER2+乳腺癌细胞信号通路的影响。研究结果显示aCT1具有广泛的结合蛋白网络，其中多数参与基因表达与RNA生物学调控。nCounter分析表明aCT1能显著影响多条信号通路，包括上调凋亡相关因子，由此预测并证实aCT1能增强顺铂和拉帕替尼对HER2靶向药物耐药型HER2+乳腺癌细胞的杀伤作用。

原文链接：

Mapping the Anti-Cancer Activity of α-Connexin Carboxyl-Terminal (aCT1) Peptide in Resistant HER2+ Breast Cancer