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Low-dose endothelial monocyte-activating polypeptide-II increases permeability of blood-tumor barrier via a PKC-ζ/PP2A-dependent signaling mechanism.

Abstract
Our previous study demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) induces blood-tumor barrier (BTB) opening via the RhoA/Rho kinase/protein kinase C (PKC)-α/β signaling pathway and that PKC-ζ is involved in this process via other mechanisms. In the present study, using an in vitro BTB model, we detected the exact signaling mechanisms by which PKC-ζ activation affects EMAP-II-induced BTB hyperpermeability. Our results showed that three types of serine/threonine (Ser/Thr) protein phosphatases (PPs), namely PP1, PP2A, and PP2B, were expressed by rat brain microvascular endothelial cells (RBMECs). There was an interaction between PKC-ζ and PP2A in RBMECs. In addition, EMAP-II induced a significant increase in both the expression and the activity of PP2A in RBMECs. Inhibition of PKC-ζ with PKC-ζ pseudosubstrate inhibitor (PKC-ζ-PI) completely blocked EMAP-II-induced PP2A activation. Conversely, inhibition of PP2A with okadaic acid (OA) had no effect on EMAP-II-induced PKC-ζ activation. Like PKC-ζ-PI, OA partially prevented EMAP-II-induced BTB hyperpermeability and occludin redistribution in RBMECs. Neither PKC-ζ-PI nor OA affected EMAP-II-induced phosphorylation of myosin light chain and redistribution of actin cytoskeleton in RBMECs. Taken together, our present study demonstrated that low-dose EMAP-II increases BTB permeability by activating the PKC-ζ/PP2A signaling pathway, which consequently leads to the disruption of TJs and impairment of endothelial barrier function.
AuthorsZhen Li, Yun-Hui Liu, Xiao-Bai Liu, Yi-Xue Xue, Ping Wang, Li-Bo Liu
JournalExperimental cell research (Exp Cell Res) Vol. 331 Issue 2 Pg. 257-66 (Feb 15 2015) ISSN: 1090-2422 [Electronic] United States
PMID25592443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Cytokines
  • Enzyme Inhibitors
  • Myosin Light Chains
  • Neoplasm Proteins
  • Occludin
  • RNA-Binding Proteins
  • small inducible cytokine subfamily E, member 1
  • Okadaic Acid
  • protein kinase C zeta
  • Protein Kinase C
  • Protein Phosphatase 1
  • Protein Phosphatase 2
Topics
  • Actin Cytoskeleton (metabolism)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Brain Neoplasms (pathology)
  • Cytokines (pharmacology)
  • Electric Impedance
  • Endothelial Cells (metabolism)
  • Enzyme Inhibitors (pharmacology)
  • Glioma (pathology)
  • Myosin Light Chains (metabolism)
  • Neoplasm Proteins (pharmacology)
  • Occludin (metabolism)
  • Okadaic Acid (pharmacology)
  • Permeability (drug effects)
  • Phosphorylation (drug effects)
  • Protein Binding
  • Protein Kinase C (antagonists & inhibitors, metabolism)
  • Protein Phosphatase 1 (biosynthesis)
  • Protein Phosphatase 2 (antagonists & inhibitors, biosynthesis, metabolism)
  • RNA-Binding Proteins (pharmacology)
  • Rats
  • Rats, Wistar
  • Signal Transduction (drug effects)
  • Tight Junctions (drug effects, pathology)
  • Tumor Cells, Cultured

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