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connexin_43

Connexin 43 (Cx43)

Connexin 43 (CX43), a protein that forms gap junction channels and hemichannels in astrocytes.


Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury 1).


It is downregulated in high-grade gliomas. Its relevance for glioma therapy has been thoroughly explored; however, its positive effects on proliferation are counterbalanced by its effects on migration and invasion. Here, we show that a cell-penetrating peptide based on CX43 (TAT-Cx43266-283) inhibited c-Src and focal adhesion kinase (FAK) and upregulated phosphatase and tensin homolog in glioma stem cells (GSCs) derived from patients. Consequently, TAT-Cx43266-283 reduced GSC motility, as analyzed by time-lapse microscopy, and strongly reduced their invasive ability. Interestingly, we investigated the effects of TAT-Cx43266-283 on freshly removed surgical specimens as undissociated glioblastoma blocks, which revealed a dramatic reduction in the growth, migration, and survival of these cells. In conclusion, a region of CX43 (amino acids 266-283) exerts an important anti-tumor effect in patient-derived glioblastoma models that includes impairment of GSC migration and invasion 2).


Human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumor necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis 3).

1)
Ichkova A, Fukuda AM, Nishiyama N, Paris G, Obenaus A, Badaut J. Small Interference RNA Targeting Connexin-43 Improves Motor Function and Limits Astrogliosis After Juvenile Traumatic Brain Injury. ASN Neuro. 2019 Jan-Dec;11:1759091419847090. doi: 10.1177/1759091419847090. PubMed PMID: 31194577.
2)
Jaraíz-Rodríguez M, Tabernero MD, González-Tablas M, Otero A, Orfao A, Medina JM, Tabernero A. A Short Region of Connexin43 Reduces Human Glioma Stem Cell Migration, Invasion, and Survival through Src, PTEN, and FAK. Stem Cell Reports. 2017 Jul 3. pii: S2213-6711(17)30270-9. doi: 10.1016/j.stemcr.2017.06.007. [Epub ahead of print] PubMed PMID: 28712848.
3)
Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, Jacob LS, Patwa R, Shah H, Xu K, Cross JR, Massagué J. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature. 2016 May 18;533(7604):493-8. doi: 10.1038/nature18268. PubMed PMID: 27225120; PubMed Central PMCID: PMC5021195.
connexin_43.txt · Last modified: 2019/06/15 09:43 by administrador