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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).

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.
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.
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