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

Li, Zhen; Liu, Yunhui; Liu, Xiao-bai; Xue, Yixue; Wang, Ping; Li, Libo

doi:10.1016/j.yexcr.2014.12.021

Cited by 16 publications

(10 citation statements)

References 34 publications

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“…These differential effects of NMII activity on endothelial cell–cell junctions are also observed in cancer metastasis, where tumor cells increase endothelial NMII activity, disrupting adhesions and allowing for transcellular migration and tissue invasion ( Khuon et al, 2010 ; Li and Zhu, 2015 ; Li et al, 2015a ). For example, melanoma cells increase endothelial cell contractility in vitro , leading to the rupture of cell–cell adhesion by the simultaneous activation of VCAM and IL1β- and IL8-mediated signaling pathways ( Weidert et al, 2014 ).…”

Section: Myosin and Vascular Diseasesmentioning

confidence: 82%

Non-muscle myosin II in disease: mechanisms and therapeutic opportunities

Litwa

Horwitz

Lamers

2015

Disease Models &Amp; Mechanisms

125

115

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The actin motor protein non-muscle myosin II (NMII) acts as a master regulator of cell morphology, with a role in several essential cellular processes, including cell migration and post-synaptic dendritic spine plasticity in neurons. NMII also generates forces that alter biochemical signaling, by driving changes in interactions between actin-associated proteins that can ultimately regulate gene transcription. In addition to its roles in normal cellular physiology, NMII has recently emerged as a critical regulator of diverse, genetically complex diseases, including neuronal disorders, cancers and vascular disease. In the context of these disorders, NMII regulatory pathways can be directly mutated or indirectly altered by disease-causing mutations. NMII regulatory pathway genes are also increasingly found in disease-associated copy-number variants, particularly in neuronal disorders such as autism and schizophrenia. Furthermore, manipulation of NMII-mediated contractility regulates stem cell pluripotency and differentiation, thus highlighting the key role of NMII-based pharmaceuticals in the clinical success of stem cell therapies. In this Review, we discuss the emerging role of NMII activity and its regulation by kinases and microRNAs in the pathogenesis and prognosis of a diverse range of diseases, including neuronal disorders, cancer and vascular disease. We also address promising clinical applications and limitations of NMII-based inhibitors in the treatment of these diseases and the development of stem-cell-based therapies.

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Section: Myosin and Vascular Diseasesmentioning

confidence: 82%

Non-muscle myosin II in disease: mechanisms and therapeutic opportunities

Litwa

Horwitz

Lamers

2015

Disease Models &Amp; Mechanisms

125

115

View full text Add to dashboard Cite

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“…In the present study, EMAP II expression was significantly increased at all time points following SE, while the expression of ZO-1 and occludin proteins decreased. It has been reported that a low expression of EMAP II could selectively increase blood-tumor barrier (BTB) permeability via a transcellular pathway through the RhoA/Rho kinase signaling pathway (35). EMAP II has also been reported to decrease the levels of tight junction-related proteins, ZO-1 and occluding, through the RhoA/ROcK and PKc signaling pathways in rat brain microvascular endothelial cells (BMEcs) (36,37).…”

Section: Discussionmentioning

confidence: 99%

Changes in the expression of endothelial monocyte‑activating polypeptide II in the rat hippocampus following status epilepticus

Zhao

et al. 2020

Int J Mol Med

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Endothelial monocyte-activating polypeptide II (EMAP II) is a sensitive marker of neurotoxic injury, the expression of which increases significantly under conditions of stress, such as hypoxia or apoptosis. Studies have confirmed the extensive apoptosis of nerve cells in the brain following status epilepticus (SE), and the occurrence of SE can confer a hypoxic state on cells. The purpose of the present study was to observe the changes in the expression of EMAP II, and in the numbers and tight junction protein levels of microvascular endothelial cells in the hippocampus of rats with pilocarpine-induced SE. The protein expression levels of EMAP II, cd31, zonula occludens 1 (ZO-1) and occludin in the hippocampus were determined by immunofluorescence and western blot analyses. It was found that almost 75.6% of the rats in the SE group developed Racine stage IV-V seizures at approximately 44.7±18.8 min after the pilocarpine administration, and the 24-h mortality rate was almost 10.4%. The weight of the rats in the SE group was significantly decreased within 24 h following SE. Immunofluorescence staining revealed a low EMAP II expression in the hippocampus of the rats in the control group; however, the numbers of EMAP II-positive cells were significantly increased in the SE group from 2 h to 21 days. The trend of EMAP II protein expression was consistent with that obtained with immunofluorescence staining. The numbers of CD31-positive microvascular endothelial cells were significantly increased from 24 h to 21 days compared with the levels in the control group. The protein expression of ZO-1 and occludin was most significantly decreased in the SE group. On the whole, the present study demonstrated that the expression of EMAP II in the rat hippocampus was upregulated in the SE model, which may promote angiogenesis and alter the TJ integrity of brain microvascular endothelial cells, with an increased number of cd31-positive microvascular endothelial cells and a decreased expression of ZO-1 and occludin.

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“…Studies have found that down-regulation of claudin-1 expression is induced by TNF-α is regulated by the PKCδ–iPLA2–PGE2–PPARγ signaling cascade in human lung carcinoma A549 cells, which caused the change of morphology and migration ability (Iitaka et al, 2015 ). EMAP-II increases BTB permeability by activating PKC-α and PKC-β (Li et al, 2015c ). TJ related proteins ZO-1, occludin and claudin-5 have a plurality of PKC phosphorylation sites.…”

Section: Discussionmentioning

confidence: 99%

“…EMAP-II alone or combined with rapamycin can inhibit the viability, migration and invasion of glioma cells through inducing autophagy (Ma et al, 2015 ; Chen et al, 2016 ). Studies have reported that low-dose EMAP-II (0.05 nM) selectively increases the permeability of BTB via the cAMP/PKA signaling pathway and the PKC-ζ/PP2A signaling pathway (Li et al, 2015a , c ). In vitro BTB model, low-dose EMAP-II can bind to α-ATP synthase on BMECs surface and open tight junction (TJ) to selectively increase the permeability of BTB by significantly decreasing the protein expression levels of TJ-related proteins ZO-1, occludin and claudin-5 (Xie et al, 2010 ; Li et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of miR-330-3p/PKC-α Signaling Pathway in Low-Dose Endothelial-Monocyte Activating Polypeptide-II Increasing the Permeability of Blood-Tumor Barrier

Liu

Chao

et al. 2017

Front. Cell. Neurosci.

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This study was performed to determine whether EMAP II increases the permeability of the blood-tumor barrier (BTB) by affecting the expression of miR-330-3p as well as its possible mechanisms. We determined the over-expression of miR-330-3p in glioma microvascular endothelial cells (GECs) by Real-time PCR. Endothelial monocyte-activating polypeptide-II (EMAP-II) significantly decreased the expression of miR-330-3p in GECs. Pre-miR-330-3p markedly decreased the permeability of BTB and increased the expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5, however, anti-miR-330-3p had the opposite effects. Anti-miR-330-3p could enhance the effect of EMAP-II on increasing the permeability of BTB, however, pre-miR-330-3p partly reversed the effect of EMAP-II on that. Similarly, anti-miR-330-3p improved the effects of EMAP-II on increasing the expression levels of PKC-α and p-PKC-α in GECs and pre-miR-330-3p partly reversed the effects. MiR-330-3p could target bind to the 3′UTR of PKC-α. The results of in vivo experiments were similar to those of in vitro experiments. These suggested that EMAP-II could increase the permeability of BTB through inhibiting miR-330-3p which target negative regulation of PKC-α. Pre-miR-330-3p and PKC-α inhibitor decreased the BTB permeability and up-regulated the expression levels of ZO-1, occludin and claudin-5 while anti-miR-330-3p and PKC-α activator brought the reverse effects. Compared with EMAP-II, anti-miR-330-3p and PKC-α activator alone, the combination of the three combinations significantly increased the BTB permeability. EMAP-II combined with anti-miR-330-3p and PKCα activator could enhance the DOX’s effects on inhibiting the cell viabilities and increasing the apoptosis of U87 glioma cells. Our studies suggest that low-dose EMAP-II up-regulates the expression of PKC-α and increases the activity of PKC-α by inhibiting the expression of miR-330-3p, reduces the expression of ZO-1, occludin and claudin-5, and thereby increasing the permeability of BTB. The results can provide a new strategy for the comprehensive treatment of glioma.

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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

Cited by 16 publications

References 34 publications

Non-muscle myosin II in disease: mechanisms and therapeutic opportunities

Non-muscle myosin II in disease: mechanisms and therapeutic opportunities

Changes in the expression of endothelial monocyte‑activating polypeptide II in the rat hippocampus following status epilepticus

The Role of miR-330-3p/PKC-α Signaling Pathway in Low-Dose Endothelial-Monocyte Activating Polypeptide-II Increasing the Permeability of Blood-Tumor Barrier

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