Sustained MARCKS Phosphorylation Contributes to Tobacco Smoke-Enhanced Lung Cancer Malignancy through EGFR-ERK Signaling
Authors: Ching-Hsien Chen, Lon Wolf R. Fong, Kent E. Pinkerton, Reen Wu
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

A110 THORACIC CANCERS: PATHOGENESIS AND NOVEL TARGETS / Poster Discussion Session / Sunday, May 17/2:15 PM-4:15 PM / Room 501-502 (Street Level) Colorado Convention Center Sustained Marcks Phosphorylation Contributes To Tobacco Smoke-Enhanced Lung Cancer Malignancy Through EGFR-Erk Signaling C.-H. Chen1 , 2 , L. Fong 1 , K. E. Pinkerton 3 , R. Wu 1 1 University of California Davis, Davis, CA, 2 , 3 University of California at Davis, Davis, CA Corresponding author's email: jchchen@ucdavis.edu Rationale : Exposure to tobacco smoke is a major risk factor for lung cancer development and progression. Although many carcinogenesis-associated pathways have been discovered, how tobacco smoke activates these pathways in promoting cancer malignancy remains poorly understood. Previously, we identified up-regulation of phospho rylated m yristoylated a lanine- r ich C k inase s ubstrate (phospho-MARCKS) as a novel predictor of lung cancer malignancy. In this study, we aimed to determine if persistent elevation of phospho-MARCKS (ser159 and ser163) results from exposure to tobacco smoke and serves as a key player in smoke-related lung cancer. Methods : The clinical relevance of phospho-MARCKS in smoke-related lung cancer was first confirmed. Next, we examined the effect of smoke exposure on phospho-MARCKS levels in airway epithelium and lung cancer. We also used genetic approaches to verify the functionality and molecular mechanism of smoke-induced phospho-MARCKS. Finally, lung cancer cells with smoke exposure were pharmacologically inhibited for MARCKS activity and then subjected to functional bio-assays. Results : Strong phospho-MARCKS staining was observed in lung cancer specimens from smokers and was positively correlated, as compared to non-smokers (n=122, P <0.001). Particularly, high phospho-MARCKS levels were significantly associated with higher smoking pack-year (n=110, P <0.01) and poor survival (n=110, P =0.04) in lung cancer patients with smoking history. We found that MARCKS becomes activated in airway epithelium and lung cancer in response to tobacco smoke, both in vitro and in vivo . Functionally, tobacco smoke-triggered elevation of phospho-MARCKS was demonstrated to act in parallel with activation of the EGFR-ERK pathway and to promote malignant progression of lung cancer cells including cancer cell growth, invasion and migration. Of note, through treatment with an inhibitor of phospho-MARCKS, the MPS peptide, we showed that suppression of smoke-induced MARCKS activity was able to down-regulate EGFR-ERK signaling and reverse malignant changes of lung cancer cells. Conclusions : Our data suggest that MARCKS phosphorylation functions in smoke-mediated lung cancer progression and also provide a potential biomarker for predicting prognosis and malignant behavior in smoke-related lung cancer. figure 1.jpg This abstract is funded by: NIH HL077902, HL096373 and California TRDRP 23FT-0104 Am J Respir Crit Care Med 191;2015:A2410