title: 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.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning Province, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang 110004, Liaoning Province, PR China. Electronic address: liuyh@sj-hospital.org.
authors.forename: Yun-Hui
authors.initials: YH
authors.lastname: Liu
authors.affiliation: The 96th Class, 7-Year Program, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Xiao-Bai
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, Liaoning Province, PR China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Yi-Xue
authors.initials: YX
authors.lastname: Xue
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, Liaoning Province, PR China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, Liaoning Province, PR China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, Liaoning Province, PR China.
authors.forename: Li-Bo
authors.initials: LB
authors.lastname: Liu
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology*; D017097:Electric Impedance; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D009363:Neoplasm Proteins / Q000494:pharmacology*; D062793:Occludin / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000096:biosynthesis; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000099221:Protein Kinase C zeta
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D018994:Myosin Light Chains; D009363:Neoplasm Proteins; D062793:Occludin; D019319:Okadaic Acid; D011493:Protein Kinase C; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D016601:RNA-Binding Proteins; D000099221:Protein Kinase C zeta; C077219:small inducible cytokine subfamily E, member 1
keywords: Blood–tumor barrier; Endothelial monocyte-activating polypeptide-II; Occludin; PKC-ζ; PP2A; Permeability