MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer

• Published in: Theranostics Vol. 11; no. 9; pp. 4122 - 4136
• Main Authors: Liu, Jun, Chen, Szu-Jung, Hsu, Ssu-Wei, Zhang, Jun, Li, Ji-Min, Yang, David C, Gu, Shenwen, Pinkerton, Kent E, Chen, Ching-Hsien
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 2021; Ivyspring International Publisher
• Subjects: A549 Cells; Animals; Cancer therapies; Cell culture; Cell Line, Tumor; Cigarette Smoking - adverse effects; Cigarettes; Epidermal growth factor; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - physiology; Flow cytometry; Humans; Kinases; Lung cancer; Lung Neoplasms - chemically induced; Lung Neoplasms - metabolism; Metastasis; Myristoylated Alanine-Rich C Kinase Substrate - metabolism; NF-kappa B - metabolism; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - physiology; Primates; Proteins; Repressor Proteins - metabolism; Research Paper; Signal Transduction - drug effects; Signal Transduction - physiology; Smoke - adverse effects; Smoking; Tobacco smoke; Tumorigenesis; Wound healing; cigarette smoking; lung cancer; NKAP; NF-κB; MARCKS
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.53558

Cigarette smoking is a major risk factor for lung cancer development and progression; however, the mechanism of how cigarette smoke activates signaling pathways in promoting cancer malignancy remains to be established. Herein, we aimed to determine the contribution of a signaling protein, myristoylated alanine-rich C kinase substrate (MARCKS), in smoke-mediated lung cancer. We firstly examined the levels of phosphorylated MARCKS (phospho-MARCKS) in smoke-exposed human lung cancer cells and specimens as well as non-human primate airway epithelium. Next, the MARCKS-interactome and its gene networks were identified. We also used genetic and pharmacological approaches to verify the functionality and molecular mechanism of smoke-induced phospho-MARCKS. We observed that MARCKS becomes activated in airway epithelium and lung cancer cells in response to cigarette smoke. Functional proteomics revealed MARCKS protein directly binds to NF-κB-activating protein (NKAP). Following MARCKS phosphorylation at ser159 and ser163, the MARCKS-NKAP interaction was inhibited, leading to the activation of NF-κB signaling. In a screen of two cohorts of lung cancer patients, we confirmed that phospho-MARCKS is positively correlated with phospho-NF-κB (phospho-p65), and poor survival. Surprisingly, smoke-induced phospho-MARCKS upregulated the expression of pro-inflammatory cytokines, epithelial-mesenchymal transition, and stem-like properties. Conversely, targeting of MARCKS phosphorylation with MPS peptide, a specific MARCKS phosphorylation inhibitor, suppressed smoke-mediated NF-κB signaling activity, pro-inflammatory cytokines expression, aggressiveness and stemness of lung cancer cells. Our results suggest that phospho-MARCKS is a novel NF-kB activator in smoke-mediated lung cancer progression and provide a promising molecular model for developing new anticancer strategies.