期刊
CANCER LETTERS
卷 532, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2022.215585
关键词
Metastasis; Non-small cell lung cancer; Diacylglycerol kinase alpha; Epithelial-mesenchymal transition; Angiogenesis
类别
资金
- National Natural Science Foundation of China [82072611, 81872012, 81872387, 82103220, 82103271, 81802719]
- Guangdong Fundamental and Applied Fundamental Research Fund [2021A1515110959]
DGKA is upregulated in the metastatic lesions of NSCLC and correlated with poor survival. It interacts with SRC and FAK proteins and activates the DGKA/SRC/FAK complex, initiating downstream signaling pathways and promoting EMT and angiogenesis in NSCLC. DGKA knockdown or pharmacologic inhibition can suppress the metastasis of NSCLC cells.
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 inter-acted 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/beta-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. Phar-macologic 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.
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