title: Serine phosphorylation of vasodilator-stimulated phosphoprotein (VASP) regulates colon cancer cell survival and apoptosis.
abstract: OBJECTIVE
  In colon cancer, disease recurrence and death are associated with abnormal tumor cell survival. Vasodilator-stimulated phosphoprotein (VASP) is an actin binding protein regulating cell shape and polarity through the F-actin cytoskeleton, whose activity is controlled by cAMP-dependent phosphorylation at Ser157 and cGMP-dependent phosphorylation at Ser239. This study examined the role of differential VASP Ser phosphorylation in regulating cell survival and apoptosis in human colon carcinoma cells.
  
  
  METHODS
  Selective inhibition of VASP Ser157 or Ser239 phosphorylation in colon cancer cells was performed with specific phosphomutant constructs. F-actin organization was examined by confocal microscopy, and the balance of cell survival and death assessed by measuring acridine orange and ethidium bromide staining, caspase-3 and BAD-pS112 expression and DNA fragmentation.
  
  
  RESULTS
  In human colon carcinoma cells suppression of VASP Ser157 phosphorylation reduced F-actin content and survival and increased apoptosis, while inhibition of VASP Ser239 phosphorylation increased F-actin content and survival and reduced cell death. Also, while 8Br-cAMP induced VASP Ser157 phosphorylation and reduced cell death, treatments with 8CPT-cGMP elevated VASP Ser239 phosphorylation and promoted apoptosis.
  
  
  CONCLUSIONS
  These findings suggest that differential VASP Ser phosphorylation represents a unique therapeutic target to control cell survival and death behavior in colon cancer. In particular, pharmacological manipulation of VASP Ser phosphorylation could be exploited to affect the malignant actin cytoskeleton and induce apoptosis in colorectal cancer cells.
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH, USA; Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: mehboob.ali@nationwidechildrens.org.
authors.forename: Mehboob
authors.initials: M
authors.lastname: Ali
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH, USA; Department of Pediatrics, Ohio State University, Columbus, OH, USA.
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Giovanni M
authors.initials: GM
authors.lastname: Pitari
mesh_terms: D000165:Acridine Orange; D000199:Actins / Q000737:chemistry; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D003110:Colonic Neoplasms / Q000378:metabolism*; D053938:DNA Fragmentation; D004996:Ethidium; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000199:Actins; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D012694:Serine; D053148:Caspase 3; D004996:Ethidium; D000165:Acridine Orange
keywords: Actin cytoskeleton; Apoptosis; Colon cancer; Ser phosphorylation; Vasodilator-stimulated phosphoprotein