Author of

• 12418

  +

  P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12426

    +

    P3.05-008 - Novel anti-cancer properties of a MARCKS ED domain peptide occur through unique alterations of PI3K/AKT signaling (ID 1720)

    09:30 - 09:30  |  Author(s): P. Thai
    • Abstract

    Background
    Constitutive activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway has been found in non–small cell lung cancer (NSCLC) and promotes cancer progression. Myristoylated alanine-rich C kinase substrates (MARCKS) is a substrate of protein kinase C (PKC), and acts as a key regulatory protein controlling cell motility and signaling. We previously reported that elevated MARCKS phosphorylation (pSer159/163) potentiates lung cancer cell malignancy by upregulation of AKT/Slug axis.

    Methods
    Tissue array and immunohistochemistry were performed to analyze MARCKS phosphorylation in 110 pairs of NSCLC tumor cells and corresponding normal tissues. The enforced and silenced expressions of MARCKS were performed in lung cancer cells to verify the role of MARCKS expression and its phosphorylation. In vitro and in vivo anticancer activities of a MARCKS ED domain peptide (MPS) were confirmed by MTS, colony formation, flow cytometry, invasion, migration assays and in vivo subcutaneous and orthotopic implantation. The molecules regulated by MPS peptide were determined by Western blotting, PIP3 pool assay and co-immunoprecipitation.

    Results
    We demonstrated that elevated MARCKS phosphorylation is correlated with advanced-stage and lymph node metastasis of lung cancer. siRNA knockdown of MARCKS expression confirmed the importance of MARCKS and its phosphorylation in modulating PIP3 pool and cancer cell survival. Furthermore, we have identified that a small peptide, MPS, which mimics the basic effector domain (ED) of MARCKS is very effective in suppressing phospho-MARCKS and PIP3 levels in lung cancer cells. MPS peptide treatment is able to inhibit cancer cell viability, colony formation, migration and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Interestingly, MPS peptide is very cytotoxic to cancer cells with highly activating PI3K/AKT signaling and malignant phenotypes, while MPS has no cytotoxic effect on normal human bronchial epithelial cells. In addition, a co-treatment of MPS peptide with epidermal growth factor receptor inhibitor erlotinib could reverse drug sensitivity of these tyrosine kinase inhibitor (TKI) resistant cells, H1650 and H1975, toward erlotinib.

    Conclusion
    These results suggest a therapeutic potential in lung cancer treatment by MPS peptide through the sequestration of PIP2 pool and the suppression of MARCKS phosphorylation and PI3K/AKT pathway.