Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis.
Yuqing LouJianlin XuYanwei ZhangWei ZhangXueyan ZhangPing GuHua ZhongHuimin WangJun LuBao-Hui HanPublished in: Cell death & disease (2021)
Epidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD). Resistance to EGFR tyrosine kinase inhibitors is a major obstacle for EGFR-mutant LUAD patients. Our gene chip array, quantitative polymerase chain reaction validation, and shRNA-based high-content screening identified the Akt kinase lanthionine synthetase C-like protein 2 (LANCL2) as a pro-proliferative gene in the EGFR-mutant LUAD cell line PC9. Therefore, we investigated whether LANCL2 plays a role in promoting cell proliferation and drug resistance in EGFR-mutant LUAD. In silico clinical correlation analysis using the Cancer Genome Atlas Lung Adenocarcinoma dataset revealed a positive correlation between LANCL2 and EGFR expression and an inverse relationship between LANCL2 gain-of-function and survival in LUAD patients. The EGFR-mutant LUAD cell lines PC9 and HCC827 displayed higher LANCL2 expression than the non-EGFR-mutant cell line A549. In addition, LANCL2 was downregulated following gefitinib+pemetrexed combination therapy in PC9 cells. LANCL2 knockdown reduced proliferation and enhanced apoptosis in PC9, HCC827, and A549 cells in vitro and suppressed murine PC9 xenograft tumor growth in vivo. Notably, LANCL2 overexpression rescued these effects and promoted gefitinib + pemetrexed resistance in PC9 and HCC827 cells. Pathway analysis and co-immunoprecipitation followed by mass spectrometry of differentially-expressed genes in LANCL2 knockdown cells revealed enrichment of several cancer signaling pathways. In addition, Filamin A and glutathione S-transferase Mu 3 were identified as two novel protein interactors of LANCL2. In conclusion, LANCL2 promotes tumorigenic proliferation, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on the positive association between LANCL2, EGFR, and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.
Keyphrases
- epidermal growth factor receptor
- small cell lung cancer
- tyrosine kinase
- advanced non small cell lung cancer
- cell cycle arrest
- signaling pathway
- induced apoptosis
- cell proliferation
- mass spectrometry
- cell death
- pi k akt
- combination therapy
- poor prognosis
- gene expression
- wild type
- ejection fraction
- genome wide
- single cell
- high resolution
- epithelial mesenchymal transition
- high throughput
- squamous cell carcinoma
- papillary thyroid
- transcription factor
- liquid chromatography
- binding protein
- young adults
- small molecule
- single molecule
- prognostic factors
- patient reported outcomes
- high performance liquid chromatography
- molecular docking
- tandem mass spectrometry
- childhood cancer