PLAG Exerts Anti-Metastatic Effects by Interfering with Neutrophil Elastase/PAR2/EGFR Signaling in A549 Lung Cancer Orthotopic Model

Abstract

The effectiveness of chemotherapy and radiotherapy to treat lung cancer is limited because of highly metastatic nature. Novel strategies and drugs to attenuate metastatic activity are urgently required. In this study, red fluorescence proteins (RFP)-labeled A549 human lung cancer cells were orthotopically implantation, where they developed primary tumors. Metastasis in brain and intestines were reduced by up to 80% by treatment with 100 mpk 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) compared with that in control mice. PLAG treatment also reduced the migration of the primary tumors. Interestingly, substantial neutrophil infiltration was observed in the tumors in control mice. The neutrophil contribution to A549 cell metastatic activity was examined in in vitro co-culture system. Metastatic activity could be achieved in the A549 cells through epidermal growth factor receptor (EGFR) transactivation mediated by protease activating receptor 2 (PAR2) receptor. Neutrophil elastase secreted from tumor-infiltrating neutrophils stimulated PAR2 and induced EGFR transactivation. However, this transactivation was inhibited by inducing PAR2 degradation following PLAG treatment and metastatic activity was effectively inhibited. PLAG attenuated cancer metastatic activity via modulated PAR2/EGFR transactivation by accelerating PAR2 degradation. These results suggest PLAG as potential therapeutic agent to combat tumor metastasis via regulating the activation signal pathway of PAR2 by tumor infiltrate-neutrophils.

Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma

“…In a previous study, we demonstrated the inhibitory effects of PLAG on tumors and tumor metastasis [45,46]. In addition, in severe inflammatory diseases due to excessive neutrophil infiltration, PLAG treatment provided symptom relief by regulating the movement of neutrophils to inflammatory lesions [47][48][49][50][51][52].…”

Suppression of tumor progression by thioredoxin-interacting protein-dependent adenosine 2B receptor degradation in a PLAG-treated Lewis lung carcinoma-1 model of non–small cell lung cancer

“…Another result of the ability of PLAG to promote receptor complex formation via TXNIP expression is the degradation of GPCRs, including PAR2, and epidermal growth factor receptor (EGFR) [ 35 , 36 ]. Internalized receptor degradation may ultimately interfere with the intracellular signaling of ligand-binding receptors.…”

“…Previous studies have shown that PLAG can effectively alleviate symptoms of severe inflammatory diseases, such as acute lung injury, oral mucositis caused by chemoradiotherapy, and gout [31] , [32] , [33] , [34] . In addition, the abnormal metastasis of A549 non–small cell lung cancer cells and the excessive growth of the triple-negative breast cancer cell line MDA-MB-231 were also effectively inhibited by PLAG [ 35 , 36 ]. Based on these results, we investigated the inhibitory effect of PLAG on tumor progression in Lewis lung carcinoma (LLC1) cell-implanted mouse models.…”

Network Pharmacology Revealed the mechanism of Platycodon grandiflorum in Lung Cancer Treatment

“…EGFR mutation played a major role in the carcinogenesis of NSCL [50,51] . EGFR could be transactivated by PAR2 receptor to achieve the transfer activity of A549 cells [52] . In previous studies, the drug resistance caused by EGFR-C797S mutations accounted for about a quarter of the sample [53] .…”