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-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. Conclusion: 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.

Tobacco smoking is a well-known risk factor for both fibrogenesis and fibrotic progression; however, the mechanisms behind these processes remain enigmatic.Receptor tyrosine kinases (RTKs) have recently been reported to drive pro-fibrotic phenotypes in fibroblasts during pulmonary fibrosis (PF). Using a phospho-RTK array screen, we identified the receptor tyrosine kinase, AXL, as a top upregulated RTK in response to smoke. Both expression and signaling activity of AXL were indeed elevated in lung fibroblasts exposed to tobacco-smoke, whereas no significant change to the levels of a canonical AXL ligand, growth arrest-specific 6 (Gas6), was seen upon smoke treatment. Notably, we found that smoke-exposed human lung fibroblasts exhibited highly proliferative and invasive activities as well as was capable of inducing fibrotic lung lesions in mice. Conversely, genetic suppression of AXL in smokeexposed fibroblasts cells led to suppression of AXL downstream pathways and aggressive phenotypes. We further demonstrated that AXL interacted with myristoylated alanine-rich C kinase substrate (MARCKS) and cooperated with MARCKS in regulating downstream signaling activity and fibroblast invasiveness.Pharmacological inhibition of AXL with AXL-specific inhibitor R428 showed selectivity for smoke-exposed fibroblasts. In all, our data suggest that AXL is a potential marker for smoke-associated PF and that targeting of the AXL pathway is a potential therapeutic strategy in treating tobacco-smoking related PF.

Aim: This study aimed to compare mortality risks across uric acid (UA) levels between non-diabetes adults and participants with diabetes and to investigate the association between hyperuricemia and mortality risks in low-risk adults. Methods: We analyzed data from adults aged >18 years without coronary heart disease and chronic kidney disease (n = 29,226) from the National Health and Nutrition Examination Survey (1999–2010) and the associated mortality data (up to December 2011). We used the Cox proportional hazards models to examine the risk of all-cause and cause-specific (cardiovascular disease (CVD) and cancer) mortality at different UA levels between adults with and without diabetes. Results: Over a median follow-up of 6.6 years, 2069 participants died (495 from CVD and 520 from cancers). In non-diabetes adults at UA ≥ 5 mg/dL, all-cause and CVD mortality risks increased across higher UA levels (p-for-trend = 0.037 and 0.058, respectively). The lowest all-cause mortality risk in participants with diabetes was at the UA level of 5–7 mg/dL. We set the non-diabetes participants with UA levels of <7 mg/dL as a reference group. Without considering the effect of glycemic control, the all-cause mortality risk in non-diabetes participants with UA levels of ≥7 mg/dL was equivalent to risk among diabetes adults with UA levels of <7 mg/dL (hazard ratio = 1.44 vs. 1.57, p = 0.49). A similar result was shown in CVD mortality risk (hazard ratio = 1.80 vs. 2.06, p = 0.56). Conclusion: Hyperuricemia may be an indicator to manage multifaceted cardiovascular risk factors in low-risk adults without diabetes, but further studies and replication are warranted.