Targeting phospho-MARCKS in smoke-mediated lung cancer

Lung cancer remains the leading cause of cancer mortality worldwide and approximately 85% of lung cancers result from smoking. Tobacco-smoke has been reported to confer not only airway epithelial cell malignancy but also lung cancer progression. Although many carcinogenesis-associated pathways have been identified, how tobacco-smoke triggers these pathways in lung cancer initiation and progression remains poorly understood. Recently, we have reported myristoylated alanine-rich C kinase substrates (MARCKS), predominantly MARCKS phosphorylation (phospho-MARCKS), as one of the risk factors associated with lung cancer invasiveness and metastasis. MARCKS is a substrate of protein kinase C (PKC) and also a membrane-associated protein. Upon phosphorylation at Ser159 and Ser163, phosphorylated MARCKS is detached from membrane and is able to regulate various cellular processes including cell migration and airway mucus granule secretion. However, there is limited information regarding the trigger of MARCKS activation.

In our preliminary work, an elevation of MARCKS phosphorylation was found in smoker’s airway epithelium and lung cancer tissues. Therefore, I hypothesize that smoke-activated MARCKS phosphorylation may contribute to malignant changes of bronchial epithelium and lung cancer. It is important to see if a persistent elevation of MARCKS phosphorylation caused by tobacco-smoke is a key player in promoting cell malignancy of airway epithelium and lung cancer. To test this hypothesis, three specific goals are proposed. My first goal is to determine whether tobacco-smoke induces MARCKS activation in airway epithelium and lung cancer. The second goal is to characterize the functional role of MARCK phosphorylation in smoke-mediated lung carcinogenesis and cancer metastasis. Finally, the focus is to confirm whether suppression of MARCKS signaling reverses malignant changes in smoke-exposed bronchial epithelial cells and lung cancer cells.

Achievement of these specific goals will define the significance of MARCKS phosphorylation in smoke-mediated lung carcinogenesis and metastasis. In addition, it will likely provide a novel biomarker for diagnosis and prognosis of smoke-related lung cancer. The long-term objective is to develop the therapeutic strategies targeting lung cancer development and progression caused by tobacco-smoke.