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A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis

Oncogene volume 33, pages 3696–3706 (2014)Cite this article

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Abstract

Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), a substrate of protein kinase C, is a key regulatory molecule controlling mucus granule secretion by airway epithelial cells as well as directed migration of leukocytes, stem cells and fibroblasts. Phosphorylation of MARKCS may be involved in these responses. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy have not been characterized. This study demonstrated elevated levels of MARCKS and phospho-MARCKS in highly invasive lung cancer cell lines and lung cancer specimens from non-small-cell lung cancer patients. siRNA knockdown of MARCKS expression in these highly invasive lung cancer cell lines reduced cell migration and suppressed PI3K (phosphatidylinositol 3′-kinase)/Akt phosphorylation and Slug level. Interestingly, treatment with a peptide identical to the MARCKS N-terminus sequence (the MANS peptide) impaired cell migration in vitro and also the metastatic potential of invasive lung cancer cells in vivo. Mechanistically, MANS peptide treatment resulted in a coordination of increase of E-cadherin expression, suppression of MARCKS phosphorylation and AKT/Slug signalling pathway but not the expression of total MARCKS. These results indicate a crucial role for MARCKS, specifically its phosphorylated form, in potentiating lung cancer cell migration/metastasis and suggest a potential use of MARCKS-related peptides in the treatment of lung cancer metastasis.

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Acknowledgements

This study was supported, in parts, by Grants from the NIH-NHLBI (HL077902, HL096373, and HL36982).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, Davis, CA, USA

    C-H Chen, P Thai, K Yoneda & R Wu

  2. Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA

    K B Adler

  3. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    P-C Yang

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  1. C-H Chen
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Correspondence to R Wu.

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Chen, CH., Thai, P., Yoneda, K. et al. A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis. Oncogene 33, 3696–3706 (2014). https://doi.org/10.1038/onc.2013.336

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