Targeting different domains of gap junction protein to control malignant glioma

Wang, Jun; Yang, Zeyu; Guo, Yufeng; Kuang, Jing‐Ya; Bian, Xiu‐Wu; Yu, Shanshan

doi:10.1093/neuonc/nox207

Cited by 27 publications

(14 citation statements)

References 97 publications

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“…Importantly, the opening and closing of GJCs or Hcs depend on their response to stimuli such as other cellular membrane channels [ 35 ]. Connexin proteins are the necessary components of GJCs and Hcs, and Cx43 is one of the most abundant members of the connexin protein family [ 36 ]. In recent years, studies have indicated that Cx43-containing GJCs and Hcs are the main cellular adhesion channels in astrocytes and maintain homeostasis of the neural microenvironment [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Cao

et al. 2020

J Neuroinflammation

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Background In the central nervous system (CNS), connexin 43 (Cx43) is mainly expressed in astrocytes and regulates astrocytic network homeostasis. Similar to Cx43 overexpression, abnormal excessive opening of Cx43 hemichannels (Cx43Hcs) on reactive astrocytes aggravates the inflammatory response and cell death in CNS pathologies. However, the role of excessive Cx43Hc opening in intracerebral hemorrhage (ICH) injury is not clear. Methods Hemin stimulation in primary cells and collagenase IV injection in C57BL/6J (B6) mice were used as ICH models in vitro and in vivo. After ICH injury, the Cx43 mimetic peptide Gap19 was used for treatment. Ethidium bromide (EtBr) uptake assays were used to measure the opening of Cx43Hcs. Western blotting and immunofluorescence were used to measure protein expression. qRT-PCR and ELISA were used to determine the levels of cytokines. Coimmunoprecipitation (Co-IP) and the Duolink in situ proximity ligation assay (PLA) were applied to measure the association between proteins. Results In this study, Cx43 expression upregulation and excessive Cx43Hc opening was observed in mice after ICH injury. Delayed treatment with Gap19 significantly alleviated hematoma volume and neurological deficits after ICH injury. In addition, Gap19 decreased inflammatory cytokine levels in the tissue surrounding the hematoma and decreased reactive astrogliosis after ICH injury in vitro and in vivo. Intriguingly, Cx43 transcriptional activity and expression in astrocytes were significantly increased after hemin stimulation in culture. However, Gap19 treatment downregulated astrocytic Cx43 expression through the ubiquitin-proteasome pathway without affecting Cx43 transcription. Additionally, our data showed that Gap19 increased Yes-associated protein (YAP) nuclear translocation. This subsequently upregulated SOCS1 and SOCS3 expression and then inhibited the TLR4-NFκB and JAK2-STAT3 pathways in hemin-stimulated astrocytes. Finally, the YAP inhibitor, verteporfin (VP), reversed the anti-inflammatory effect of Gap19 in vitro and almost completely blocked its protective effects in vivo after ICH injury. Conclusions This study provides new insight into potential treatment strategies for ICH injury involving astroglial Cx43 and Cx43Hcs. Suppression of abnormal astroglial Cx43 expression and Cx43Hc opening by Gap19 has anti-inflammatory and neuroprotective effects after ICH injury.

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Section: Discussionmentioning

confidence: 99%

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Cao

et al. 2020

J Neuroinflammation

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“…It remains to be determined if these peptides have utility in overcoming chemotherapeutic resistance in various stages or subsets of GBM cells or GSCs. An alternative strategy may involve the use of monoclonal antibodies designed against the extracellular domain of Cx43 to inhibit the connexon structure, alter GJIC and hemichannel activity, inhibit glioma invasion, and/or overcome chemoresistance (discussed in [63 • ]).…”

Section: Therapeutic Opportunity For Connexin43 Peptidomimeticsmentioning

confidence: 99%

“…The Cx43 C-terminus interacts with a number of signaling molecules including c-Src, protein kinase C, AKT serine/threonine kinase, and mitogen-activated protein kinase to name a few (reviewed in [63 • ]). These interactions can also affect the phosphorylation status of Cx43 and consequently regulate its degradation, subcellular localization, and channel assembly processes, in addition to potentially mediating GBM resistance to TMZ [64,65].…”

Section: Therapeutic Opportunity For Connexin43 Peptidomimeticsmentioning

confidence: 99%

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

Grek

Sheng

Naus

et al. 2018

Current Opinion in Pharmacology

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Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl-terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding. High levels of intra-tumor and inter-tumor heterogeneity make it difficult to clearly define specific populations for Cx43-targeted therapy; hence, development of in vitro models that better mimic the microenvironment of malignant glioma, and the incorporation of patient-derived stem cells, could provide opportunities for patient-specific drug screening. This review summarizes recent advances in understanding the roles of Cx43 in malignant glioma, with a special focus on tumor microenvironment, TMZ resistance, and therapeutic opportunity offered by Cx43 peptidomimetics.

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“…Importantly,the opening and closing of GJCs or Hcs depend on the response to stimuli such as other cellular membrane channels [31]. Connexin proteins are the necessary components of GJCs and Hcs, and Cx43 is one of the most abundant members of the connexin protein family [32]. In recent years, studies have indicated that Cx43-containing GJCs and Hcs are the main cell adhesion channels in astrocytes and maintain the homeostasis of the neural microenvironment in the CNS [10].…”

Section: Discussionmentioning

confidence: 99%

Targeting Connexin43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Cao

et al. 2020

Preprint

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Background: In the central nervous system(CNS),Connexin43 (Cx43) is mainly expressed in astrocytes and regulates astrocytic network homeostasis. Like Cx43 overexpression,abnormal excessive opening of Cx43 hemichannels (Cx43Hcs) on reactive astrocytes aggravates the inflammatory response and cell death in CNS pathologies.However, the role of excessive Cx43Hc opening in intracerebral hemorrhage (ICH) injury is not clear.Methods: Hemin stimulation in primary cells and collagenase IV injection in C57BL/6J (B6) mice were used as ICH modals in vitro and vivo.Cx43 mimetic peptide Gap19 was treated after ICH injury. Ethidium bromide (EtBr) uptake assays was used to measure the opening of Hcs. Western blot and immunofluorescence were used to measure the expression of protein. qRT-PCR and ELISA were used to determine the level of cytokines. Co-immunoprecipitation(Co-IP) and Duolink in situ proximity ligation assay (PLA) were applied to measure the association between proteins.Results: In this study,Cx43 expression was upregulated, and excessive Cx43Hc opening was observed in mice after ICH injury. Delayed treatment with Gap19significantly alleviated hematoma volume and neurological deficits after ICH injury. In addition,Gap19 decreased inflammatory cytokine levels in the tissue surrounding the hematoma and decreased reactive astrogliosis after ICH injury in vitro and in vivo, as determined by GFAP staining. Intriguingly, Cx43 transcriptional activity and expression in astrocytes were significantly increased after hemin stimulation in culture.However,Gap19 treatment downregulated astrocytic Cx43 expression through the ubiquitin-proteasome pathway without affecting Cx43 transcription. Additionally, our data showed that Gap19 increased YAP nuclear translocation, which upregulated SOCS1 and SOCS3 expression, and then inhibited the TLR4-NFκB and JAK2-STAT3 pathways in hemin-stimulated astrocytes. Finally, the YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of Gap19 in vitro and almost completely blocked its protective effects in vivo after ICH injury.Conclusions: This study provides new insight into potential treatment strategies for ICH injury involving astroglial Cx43 and Cx43Hcs.Suppression of abnormal astroglial Cx43 expression and Cx43Hc opening by Gap19 plays anti-inflammatory and neuroprotective roles after ICH injury.

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Targeting different domains of gap junction protein to control malignant glioma

Cited by 27 publications

References 97 publications

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

Targeting Connexin43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

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