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.

• Authors: Zhen Li, Yun-Hui Liu, Xiao-Bai Liu, Yi-Xue Xue, Ping Wang, Li-Bo Liu
• Journal: Experimental cell research (Exp Cell Res) Vol. 331 Issue 2 Pg. 257-66 (Feb 15 2015) ISSN: 1090-2422 [Electronic] United States
• PMID: 25592443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 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