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

Ching-Hsien Chen1, Sarah Statt, Chun-Lung Chiu

  • 11 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, Davis, California; and.

American Journal of Respiratory and Critical Care Medicine
|October 16, 2014
PubMed
Abstract

Insights

Targeting phospho-myristoylated alanine-rich C kinase substrate (phospho-MARCKS) in lung cancer shows promise. Inhibiting MARCKS phosphorylation site domain (PSD) activity suppressed tumor growth and erlotinib resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Phosphorylation of myristoylated alanine-rich C kinase substrate (phospho-MARCKS) is vital for cell functions but its role in lung cancer is unclear.
  • Elevated phospho-MARCKS levels correlate with poorer survival in lung cancer patients.

Purpose of the Study:

  • To investigate MARCKS phosphorylation site domain (PSD) activity as a therapeutic target in lung cancer.
  • To elucidate the molecular mechanisms underlying phospho-MARCKS' role in lung cancer progression and erlotinib resistance.

Main Methods:

  • Clinical relevance of phospho-MARCKS assessed.
  • Genetic manipulation (shRNA, ectopic expression) of MARCKS and its mutants used to study function.
  • Pharmacological inhibition of MARCKS PSD activity with a peptide (MPS peptide) and assessment of cancer cell functions and erlotinib sensitivity.

Main Results:

  • Higher phospho-MARCKS levels associated with shorter lung cancer patient survival.
  • Elevated phospho-MARCKS promoted tumor growth and erlotinib resistance, independent of phosphoinositide 3-kinase interaction but parallel to PI(3,4,5)P3 pools and AKT activation.
  • MPS peptide treatment suppressed tumor growth, metastasis, and erlotinib resistance in vivo and in vitro.

Conclusions:

  • MARCKS PSD plays a critical role in lung cancer pathogenesis.
  • Inhibiting MARCKS PSD activity represents a novel therapeutic strategy for lung cancer, particularly enhancing erlotinib efficacy.
Keywords:
MARCKS phosphorylationPI3K/AKTPIP3erlotiniblung cancer

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