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.
Highlights
Lung cancer has a much higher mortality rate than other cancers [1,2]
The PLAG treatment reduced the numbers of metastasized cells in the intestines, inhibiting metastasis by more than 80%
The results suggest that PLAG induced αARR, and the degradation of neutrophil-stimulated protease activating receptor 2 (PAR2) was achieved via promotion of the αARR complex including ubiquitin ligase
Summary
Lung cancer has a much higher mortality rate than other cancers [1,2]. Lung cancer is not detected at an early stage and has robust metastatic activity, which contributes to the low survival rate.Metastasized lung cancer is frequently observed in the brain, liver, and intestines, making it difficult to treat with conventional therapies [3,4,5]. Lung cancer has a much higher mortality rate than other cancers [1,2]. Lung cancer is not detected at an early stage and has robust metastatic activity, which contributes to the low survival rate. Metastasized lung cancer is frequently observed in the brain, liver, and intestines, making it difficult to treat with conventional therapies [3,4,5]. The survival rate of patients varies significantly according to the metastasis. The metastatic activity of lung carcinoma is strongly affected by overactivation of growth factors, eventually leading to metastasis and poor prognosis [6,7]. Drug development against metastasis is crucial for the treatment of lung cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
