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

被引:35
作者
Liu, Jun [1 ,2 ,3 ]
Chen, Szu-Jung [1 ,2 ,3 ]
Hsu, Ssu-Wei [1 ,2 ]
Zhang, Jun [1 ,2 ,3 ,4 ]
Li, Ji-Min [1 ,2 ,3 ]
Yang, David C. [1 ,2 ,3 ]
Gu, Shenwen [1 ,2 ,3 ]
Pinkerton, Kent E. [5 ,6 ]
Chen, Ching-Hsien [1 ,2 ,3 ,4 ]
机构
[1] Univ Calif Davis, Dept Internal Med, Div Pulm & Crit Care Med, Davis, CA 95616 USA
[2] Univ Calif Davis, Ctr Comparat Resp Biol & Med, Davis, CA 95616 USA
[3] Univ Calif Davis, Div Nephrol, Dept Internal Med, Davis, CA 95616 USA
[4] Univ Calif Davis, Comprehens Canc Ctr, Davis, CA 95616 USA
[5] Univ Calif Davis, Ctr Hlth & Environm, Davis, CA 95616 USA
[6] Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA
来源
THERANOSTICS | 2021年 / 11卷 / 09期
关键词
MARCKS; NKAP; NF-kappa B; cigarette smoking; lung cancer; C-KINASE SUBSTRATE; LONG NONCODING RNA; CIGARETTE-SMOKE; UP-REGULATION; STEM-CELLS; PHOSPHORYLATION; EXPRESSION; PROTEIN; TUMORIGENESIS; DOMAIN;
D O I
10.7150/thno.53558
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Rationale: 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. Methods: 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. Results: 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-kappa B-activating protein (NKAP). Following MARCKS phosphorylation at ser159 and ser163, the MARCKS-NKAP interaction was inhibited, leading to the activation of NF-kappa B signaling. In a screen of two cohorts of lung cancer patients, we confirmed that phospho-MARCKS is positively correlated with phospho-NF-kappa B (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-kappa B signaling activity, pro-inflammatory cytokines expression, aggressiveness and stemness of lung cancer cells. Conclusion: Our results suggest that phospho-MARCKS is a novel NF-kappa B activator in smoke-mediated lung cancer progression and provide a promising molecular model for developing new anticancer strategies.
引用
收藏
页码:4122 / 4136
页数:15
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