DGKA interacts with SRC/FAK to promote the metastasis of non-small cell lung cancer. (28th April 2022)

• Record Type: Journal Article
• Authors: Fu, Lingyi; Deng, Ru; Huang, Yuhua; Yang, Xia; Jiang, Neng; Zhou, Jing; Lin, Censhan; Chen, Shilu; Wu, Liyan; Cui, Qian; Yun, Jingping
• Is Part Of: Cancer letters. Volume 532(2022)
• Publication Date: 2022-04-28
• Subjects: Metastasis -- Non-small cell lung cancer -- Diacylglycerol kinase alpha -- Epithelial-mesenchymal transition -- Angiogenesis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215585
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Metastasis is responsible for the high mortality rate of lung cancer, but its underlying molecular mechanisms are poorly understood. Here, we demonstrated that the expression of diacylglycerol kinase alpha (DGKA) was elevated in the metastatic lesions of non-small cell lung cancer (NSCLC) and correlated with poor survival. Mechanistic studies revealed a direct physical interaction as well as a mutual regulation among DGKA, proto-oncogene tyrosine-protein kinase Src (SRC), and focal adhesion kinase 1 (FAK) proteins. The C-terminal domain of DGKA was responsible for the SRC SH3 domain binding, while the catalytic domain of DGKA interacted with the FREM domain of FAK. DGKA phosphorylated the SRC protein at Tyr416 and the FAK protein at Tyr397 to form and activate the DGKA/SRC/FAK complex, thus initiating the downstream WNT/β-catenin and VEGF signaling pathways, promoting epithelial-mesenchymal transition (EMT) and angiogenesis, and resulting in the metastasis of NSCLC. DGKA knockdown inhibited the invasive phenotype of NSCLC cells in vitro . Pharmacologic ablation of DGKA inhibited the metastasis of NSCLC cells in vivo, and this was reversed by the overexpression of DGKA . These results suggested that DGKA was a potential prognostic biomarker as well as a promising therapeutic target for NSCLC, especially when there was lymphatic or distant metastasis. Highlights: Diacylglycerol kinase alpha (DGKA) is correlated with poor survival in NSCLC. DGKA expression is elevated in the metastatic lesions of NSCLC. Mechanistic studies show physical interactions among DGKA, SRC, and FAK proteins. Pharmacologic ablation of DGKA significantly inhibits the metastasis of NSCLC. DGKA acts as a potential prognostic biomarker and promising therapeutic target.