{"doi":"10.1016/j.ebiom.2020.103205","title":"Connexin 43 peptidic medicine for glioblastoma stem cells","abstract":"The role of connexin 43 (Cx43) in glioblastoma (GBM) is perplexing, making it difficult to develop Cx43-based therapies to treat this deadly brain cancer. For instance, Cx43 has long been considered as a tumor suppressor in glioma, because Cx43, as a gap junction (GJ) protein, forms membrane channels to enhance cell-cell communication, which suppresses the formation of glioma [[1]Naus C.C. Elisevich K. Zhu D. Belliveau D.J. Del Maestro R.F. In vivo growth of C6 glioma cells transfected with connexin43 cDNA.Cancer Res. 1992; 52: 4208-4213PubMed Google Scholar]. Indeed, reduced GJ intercellular communication (GJIC) is a hallmark of cancer [[2]Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Summary Full Text Full Text PDF PubMed Scopus (38890) Google Scholar]. However, recent research–that highlights the importance of Cx43 in intertumoral and intratumoral heterogeneity in GBM–has challenged this model. A side population of GBM cells, called GBM stem cells (GSCs), has displayed considerably different traits compared to other GBM cells, one of which is the unusually strong ability to propagate a tumor in mice [[3]Singh S.K. Hawkins C. Clarke I.D. Squire J.A. Bayani J. Hide T. Henkelman R.M. Cusimano M.D. Dirks P.B. Identification of human brain tumour initiating cells.Nature. 2004; 432: 396-401Crossref PubMed Scopus (5872) Google Scholar]. This helps explain why GBM patients often succumb to a progressive and recurrent disease because GSCs, spared by surgical resection, radiation, and chemotherapy, can grow another tumor in the brain. Eliminating GSCs is therefore an appealing therapeutic approach; however, targeting GSCs is challenging given their idiosyncratic nature that makes GSCs metabolically resilient compared to differentiated tumor cells and endows GSCs survival advantages particularly under unfavorable growth conditions. Recent research from Pelaz and her colleagues has provided possible answers to this challenge and offered a new therapeutic opportunity that allows us to eliminate dormant and resilient GSCs [[4]Pelaz S.G. Jaraiz-Rodriguez M. Alvarez-Vazquez A. Talaveron R. Garcia-Vicente L. Flores-Hernandez R. Gomez de Cedron M. Tabernero M. Ramirez de Molina A. Lillo C. Medina J.M. Tabernero A. Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TAT-Cx43266-283.EBioMedicine. 2020; 62103134Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. This research stems from the finding from the Tabernero laboratory that Cx43’s carboxyl terminus (CT), located inside of cells, activates SRC proto-oncogene, non-receptor tyrosine kinase (c-SRC) in patient-derived GSCs [[5]Jaraiz-Rodriguez M. Tabernero M.D. Gonzalez-Tablas M. Otero A. Orfao A. Medina J.M. 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; 9: 451-463Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. The activation of c-SRC subsequently promotes the motility, growth, and tumorigenicity of GSCs in vitro and in vivo [[6]Gangoso E. Thirant C. Chneiweiss H. Medina J.M. Tabernero A. A cell-penetrating peptide based on the interaction between c-Src and connexin43 reverses glioma stem cell phenotype.Cell Death Dis. 2014; 5: e1023Crossref PubMed Scopus (48) Google Scholar]. Given that c-SRC plays a vital role in regulating metabolism in cancer, Pelaz et al., tested the hypothesis that Cx43-CT regulates GSCs’ metabolic activity [[4]Pelaz S.G. Jaraiz-Rodriguez M. Alvarez-Vazquez A. Talaveron R. Garcia-Vicente L. Flores-Hernandez R. Gomez de Cedron M. Tabernero M. Ramirez de Molina A. Lillo C. Medina J.M. Tabernero A. Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TAT-Cx43266-283.EBioMedicine. 2020; 62103134Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. By t","journal":"EBioMedicine","year":2021,"id":202062,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":571556,"name":"Zhi Sheng","orcid":"0000-0002-0029-8666","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-18T23:51:05.955461Z","pmid":"33493796","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}