CRMP2 is a therapeutic target that suppresses the aggressiveness of breast cancer cells by stabilizing RECK
CRMP2 is a therapeutic target that suppresses the aggressiveness of breast cancer cells by stabilizing RECK
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CRMP2 是一种治疗靶点，通过稳定 RECK 来抑制乳腺癌细胞的侵袭性
DOI：
10.1038/s41388-020-01412-x
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发表时间：
2020-08-10
期刊：
影响因子：
8
通讯作者：
Lu, Na
中科院分区：
文献类型：
--
作者：
Lin, Binyan;Li, Yongxu;Lu, Na
转移性乳腺癌的特点是死亡率高，治疗靶点有限。在肿瘤转移过程中，细胞骨架重组是乳腺癌细胞迁移和侵袭的关键步骤之一。溃缩蛋白反应介导蛋白2（CRMP 2）是一种在调节细胞骨架动力学中起重要作用的胞质磷蛋白。先前的研究已经报道了CRMP 2表达的改变与乳腺癌的进展有关，但其潜在的机制仍然知之甚少。在这里，我们发现CRMP 2表达在各种亚型的乳腺癌中减少，并与淋巴转移呈负相关。CRMP 2的过表达显著抑制乳腺癌细胞的侵袭和干性，而CRMP 2的下调促进细胞侵袭，这不是微管蛋白聚合所必需的。机制研究表明，CRMP 2与RECK相互作用，阻止RECK降解，进而阻断NF-κB和Wnt信号通路。此外，我们发现CRMP 2在T514和S522处的磷酸化显著地消除了其与RECK结合并抑制细胞侵袭的功能。CRMP 2表达的药理学拯救在体外和体内抑制了乳腺癌转移，并刺激了与FN-1501的协同作用，诱导CRMP 2去磷酸化。总的来说，这项研究突出了CRMP 2作为乳腺癌转移治疗靶点的潜力，并揭示了CRMP 2的独特机制。
Metastatic breast cancer is characterized by high mortality and limited therapeutic target. During tumor metastasis, cytoskeletal reorganization is one of the key steps in the migration and invasion of breast cancer cells. Collapsin response mediator protein 2 (CRMP2) is a cytosolic phosphoprotein that plays an important role in regulating cytoskeletal dynamics. Previous researches have reported that altered CRMP2 expression is associated with breast cancer progression, but the underlying mechanism remains poorly understood. Here, we show that CRMP2 expression is reduced in various subtypes of breast cancers and negatively correlated with lymphatic metastasis. Overexpression of CRMP2 significantly inhibits invasion and stemness in breast cancer cells, while downregulation of CRMP2 promotes cell invasion, which is not required for tubulin polymerization. Mechanistic studies demonstrate that CRMP2 interacts with RECK, prevents RECK degradation, which, in turn, blocks NF-κB and Wnt signaling pathways. Furthermore, we find that phosphorylation of CRMP2 at T514 and S522 remarkably abolishes its functions to bind with RECK and to inhibit cell invasion. Pharmacologic rescue of CRMP2 expression suppressed breast cancer metastasis in vitro and in vivo and stimulated a synergetic effect with FN-1501 that induces CRMP2 dephosphorylation. Collectively, this study highlights the potential of CRMP2 as a therapeutic target in breast cancer metastasis and reveals a distinct mechanism of CRMP2.