PLAG exerts anti-metastatic effects by interfering with neutrophil elastase/PAR2/EGFR signaling in A549 lung cancer orthotopic model

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Title
PLAG exerts anti-metastatic effects by interfering with neutrophil elastase/PAR2/EGFR signaling in A549 lung cancer orthotopic model
Author(s)
Guen Tae Kim; K W Hahn; S Y Yoon; K Y Sohn; Jae Wha Kim
Bibliographic Citation
Cancers, vol. 12, no. 3, pp. 560-560
Publication Year
2020
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.
Keyword
EGFR transactivationPAR2 degradationPLAGanti-metastasistumor infiltrated-neutrophils (TINs)
ISSN
2072-6694
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/cancers12030560
Type
Article
Appears in Collections:
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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