Wang Chunqing, Zhao Xiaoqing, Zhao Liqing, Wang Yunqiu, Jia Yan, Zhang Xiaofang, Ma Wanshan
Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Laboratory Medicine China.
Department of Clinical Laboratory Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong China.
Exp Cell Res. 2023 Dec 15;433(2):113823. doi: 10.1016/j.yexcr.2023.113823. Epub 2023 Oct 25.
Breast carcinoma (BC) is one of the most common malignant cancers in females, and metastasis remains the leading cause of death in these patients. Chemotaxis plays an important role in cancer cell metastasis and the mechanism of breast cancer chemotaxis has become a central issue in contemporary research. PKCζ, a member of the atypical PKC family, has been reported to be an essential component of the EGF-stimulated chemotactic signaling pathway. However, the molecular mechanism through which PKCζ regulates chemotaxis remains unclear. Here, we used a proteomic approach to identify PKCζ-interacting proteins in breast cancer cells and identified VASP as a potential binding partner. Intriguingly, stimulation with EGF enhanced this interaction and induced the translocalization of PKCζ and VASP to the cell membrane. Further experiments showed that PKCζ catalyzes the phosphorylation of VASP at Ser157, which is critical for the biological function of VASP in regulating chemotaxis and actin polymerization in breast cancer cells. Furthermore, in PKCζ knockdown BC cells, the enrichment of VASP at the leading edge was reduced, and its interaction with profilin1 was attenuated, thereby reducing the chemotaxis and overall motility of breast cancer cells after EGF treatment. In functional assays, PKCζ promoted chemotaxis and motility of BC cells through VASP. Our findings demonstrate that PKCζ, a new kinase of VASP, plays an important role in promoting breast cancer metastasis and provides a theoretical basis for expanding new approaches to tumor biotherapy.
乳腺癌（BC）是女性最常见的恶性肿瘤之一，转移仍然是这些患者死亡的主要原因。趋化作用在癌细胞转移中起重要作用，乳腺癌趋化作用的机制已成为当代研究的核心问题。PKCζ是非典型PKC家族的成员，据报道是表皮生长因子（EGF）刺激的趋化信号通路的重要组成部分。然而，PKCζ调节趋化作用的分子机制仍不清楚。在这里，我们使用蛋白质组学方法来鉴定乳腺癌细胞中与PKCζ相互作用的蛋白质，并确定vasodilator-stimulated phosphoprotein（VASP）为潜在的结合伴侣。有趣的是，EGF刺激增强了这种相互作用，并诱导PKCζ和VASP转位至细胞膜。进一步的实验表明，PKCζ催化VASP在Ser157位点的磷酸化，这对VASP在调节乳腺癌细胞趋化作用和肌动蛋白聚合中的生物学功能至关重要。此外，在PKCζ敲低的BC细胞中，VASP在前缘的富集减少，其与profilin1的相互作用减弱，从而降低了EGF处理后乳腺癌细胞的趋化作用和整体运动性。在功能试验中，PKCζ通过VASP促进BC细胞的趋化作用和运动性。我们的研究结果表明，PKCζ作为VASP的一种新激酶，在促进乳腺癌转移中起重要作用，并为拓展肿瘤生物治疗新方法提供了理论依据。
