title: Targeting myristoylated alanine-rich C kinase substrate phosphorylation site domain in lung cancer. Mechanisms and therapeutic implications.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 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, California; and.
authors.forename: Ching-Hsien
authors.initials: CH
authors.lastname: Chen
authors.forename: Sarah
authors.initials: S
authors.lastname: Statt
authors.forename: Chun-Lung
authors.initials: CL
authors.lastname: Chiu
authors.forename: Philip
authors.initials: P
authors.lastname: Thai
authors.forename: Muhammad
authors.initials: M
authors.lastname: Arif
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Adler
authors.forename: Reen
authors.initials: R
authors.lastname: Wu
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000069347:Erlotinib Hydrochloride; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C060974:phosphatidylinositol 3,4,5-triphosphate; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D000069347:Erlotinib Hydrochloride; D058539:Phosphatidylinositol 3-Kinase
keywords: MARCKS phosphorylation; PI3K/AKT; PIP3; erlotinib; lung cancer