Abstract
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.
Highlights
Lung cancer is the most prominent cause of cancer mortality worldwide, with lung adenocarcinoma (LUAD) accounting for around 50% of all lung cancers[1]
We evaluated the role of lanthionine synthetase C-like 2 (LANCL2) in cell proliferation and drug resistance in epidermal growth factor receptor (EGFR)-mutant LUAD using in vitro and short hairpin RNA (shRNA)-mediated LANCL2 knockdown studies
LANCL2 is a key gene contributing to PC9 cell proliferation We conducted a transcriptomic screen employing a gene chip array and follow-up quantitative RT-PCR (qPCR) validation to identify the most abundant gene transcripts in the PC9 LUAD cell line. qPCR analysis of the top 32 most-abundant gene transcripts identified from the gene chip array revealed several highly-abundant genes, including RPS4X, EIF3C, DHX9, TMEM123, and LANCL2 (Supplementary Fig. S1)
Summary
Lung cancer is the most prominent cause of cancer mortality worldwide, with lung adenocarcinoma (LUAD) accounting for around 50% of all lung cancers[1]. Clinical trial evidence suggests that EGFR-mutant LUAD patients can be effectively treated using first-line EGFR tyrosine kinase signaling and EGFR TKI resistance in EGFR-mutant. EGFR hyperactivates the serine/threonine protein kinase Akt[10,11,12,13,14,15,16], which is known to play a key role in supporting cell survival, proliferation, and glucose metabolism[17]. Akt hyperactivity is a common hallmark of a variety of human cancers, including EGFR-mutant LUAD, making it an important therapeutic target for cancer treatment[18]. The role of LANCL2 in EGFR-mutant LUAD tumorigenesis and EGFR TKI resistance (if any) has not yet been evaluated
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