State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Avenue No. 138, Nanjing, 210023, People's Republic of China.
Oncogene. 2020 Sep;39(37):6024-6040. doi: 10.1038/s41388-020-01412-x. Epub 2020 Aug 10.
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.
转移性乳腺癌的死亡率高，治疗靶点有限。在肿瘤转移过程中，细胞骨架重排是乳腺癌细胞迁移和侵袭的关键步骤之一。 collapsin 反应介质蛋白 2（CRMP2）是一种细胞质磷酸蛋白，在调节细胞骨架动力学方面发挥着重要作用。先前的研究表明，CRMP2 表达的改变与乳腺癌的进展有关，但潜在的机制仍不清楚。在这里，我们表明 CRMP2 的表达在各种亚型的乳腺癌中降低，并且与淋巴转移呈负相关。CRMP2 的过表达显著抑制乳腺癌细胞的侵袭和干性，而 CRMP2 的下调促进细胞侵袭，这并不需要微管聚合。机制研究表明，CRMP2 与 RECK 相互作用，阻止 RECK 的降解，从而阻断 NF-κB 和 Wnt 信号通路。此外，我们发现 CRMP2 在 T514 和 S522 的磷酸化显著削弱了其与 RECK 结合和抑制细胞侵袭的功能。药理学恢复 CRMP2 的表达抑制了乳腺癌在体外和体内的转移，并与 FN-1501 产生协同作用，FN-1501 诱导 CRMP2 的去磷酸化。总之，这项研究强调了 CRMP2 作为治疗乳腺癌转移的潜在靶点的重要性，并揭示了 CRMP2 的一个独特机制。
