Targeting myristoylated alanine-rich C kinase substrate phosphorylation site domain in lung cancer. Mechanisms and therapeutic implications

Am J Respir Crit Care Med. 2014 Nov 15;190(10):1127-38. doi: 10.1164/rccm.201408-1505OC.


Rationale: Phosphorylation of myristoylated alanine-rich C kinase substrate (phospho-MARCKS) at the phosphorylation site domain (PSD) is crucial for mucus granule secretion and cell motility, but little is known concerning its function in lung cancer.

Objectives: We aimed to determine if MARCKS PSD activity can serve as a therapeutic target and to elucidate the molecular basis of this potential.

Methods: The clinical relevance of phospho-MARCKS was first confirmed. Next, we used genetic approaches to verify the functionality and molecular mechanism of phospho-MARCKS. Finally, cancer cells were pharmacologically inhibited for MARCKS activity and subjected to functional bioassays.

Measurements and main results: We demonstrated that higher phospho-MARCKS levels were correlated with shorter overall survival of lung cancer patients. Using shRNA silencing and ectopic expression of wild-type and PSD-mutated (S159/163A) MARCKS, we showed that elevated phospho-MARCKS promoted cancer growth and erlotinib resistance. Further studies demonstrated an interaction of phosphoinositide 3-kinase with MARCKS, but not with phospho-MARCKS. Interestingly, phospho-MARCKS acted in parallel with increased phosphatidylinositol (3,4,5)-triphosphate pools and AKT activation in cells. Through treatment with a 25-mer peptide targeting the MARCKS PSD motif (MPS peptide), we were able to suppress tumor growth and metastasis in vivo, and reduced levels of phospho-MARCKS, phosphatidylinositol (3,4,5)-triphosphate, and AKT activity. This peptide also enhanced the sensitivity of lung cancer cells to erlotinib treatment, especially those with sustained activation of phosphoinositide 3-kinase/AKT signaling.

Conclusions: These results suggest a key role for MARCKS PSD in cancer disease and provide a unique strategy for inhibiting the activity of MARCKS PSD as a treatment for lung cancer.

Keywords: MARCKS phosphorylation; PI3K/AKT; PIP3; erlotinib; lung cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Disease Models, Animal
  • Erlotinib Hydrochloride
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Membrane Proteins / metabolism*
  • Mice
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphorylation / physiology
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolines / therapeutic use
  • Signal Transduction / physiology


  • Intracellular Signaling Peptides and Proteins
  • MARCKS protein, human
  • Marcks protein, mouse
  • Membrane Proteins
  • Phosphatidylinositol Phosphates
  • Protein Kinase Inhibitors
  • Quinazolines
  • phosphatidylinositol 3,4,5-triphosphate
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Erlotinib Hydrochloride
  • Phosphatidylinositol 3-Kinase