Role of ATP synthase alpha subunit in low-dose endothelial monocyte-activating polypeptide-II-induced opening of the blood-tumor barrier

J Neurol Sci. 2011 Jan 15;300(1-2):52-8. doi: 10.1016/j.jns.2010.09.034. Epub 2010 Oct 28.

Abstract

This study was performed to determine whether the α subunit of ATP synthase (α-ATP synthase) on brain microvascular endothelial cells (BMECs) serves as the functional target for endothelial monocyte-activating polypeptide-II (EMAP-II)-induced increase in blood-tumor barrier (BTB) permeability. Using a rat C6 glioma model, we found that low-dose (80 ng/kg) EMAP-II significantly decreased the mRNA and protein expression levels of tight junction (TJ)-related proteins claudin-5, occludin, and ZO-1 on BMECs. Meantime, radioimmunity and Western blot assay showed a significant decrease in the expression levels of cAMP and catalytic subunit of protein kinase A (PKAcs) of tumor tissues. Also, pretreatment with specific α-ATP synthase antibody significantly blocked the effects of EMAP-II on TJ-related proteins, cAMP, and PKAcs. In addition, double immunofluorescence assay identified that EMAP-II was co-localized with α-ATP synthase on BMECs. This in vivo study demonstrated that α subunit of ATP synthase on BMECs serves as the functional target for EMAP-II selective opening of the BTB, and that cAMP/PKA signaling transduction pathway might be involved in the modulating process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / blood supply
  • Brain / metabolism
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology*
  • Cell Line, Tumor
  • Claudin-5
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / metabolism
  • Cytokines / pharmacology*
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Evans Blue / metabolism
  • Glioma / blood supply
  • Glioma / metabolism*
  • Male
  • Membrane Proteins / metabolism
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
  • Mitochondrial Proton-Translocating ATPases / physiology*
  • Neoplasm Proteins / pharmacology*
  • Occludin
  • Phosphoproteins / metabolism
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / physiology
  • Proton-Translocating ATPases / antagonists & inhibitors
  • Proton-Translocating ATPases / drug effects
  • Proton-Translocating ATPases / physiology*
  • RNA-Binding Proteins / pharmacology*
  • Rats
  • Rats, Wistar
  • Zonula Occludens-1 Protein

Substances

  • Claudin-5
  • Cldn5 protein, rat
  • Cytokines
  • Membrane Proteins
  • Neoplasm Proteins
  • Occludin
  • Ocln protein, rat
  • Phosphoproteins
  • Protein Subunits
  • RNA-Binding Proteins
  • Tjp1 protein, rat
  • Zonula Occludens-1 Protein
  • small inducible cytokine subfamily E, member 1
  • Evans Blue
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • Mitochondrial Proton-Translocating ATPases
  • Proton-Translocating ATPases