title: Connexin 43 Inhibition Sensitizes Chemoresistant Glioblastoma Cells to Temozolomide.
abstract: Resistance of glioblastoma (GBM) to the front-line chemotherapeutic agent temozolomide (TMZ) continues to challenge GBM treatment efforts. The repair of TMZ-induced DNA damage by O-6-methylguanine-DNA methyltransferase (MGMT) confers one mechanism of TMZ resistance. Paradoxically, MGMT-deficient GBM patients survive longer despite still developing resistance to TMZ. Recent studies indicate that the gap junction protein connexin 43 (Cx43) renders GBM cells resistant to TMZ through its carboxyl terminus (CT). In this study, we report insights into how Cx43 promotes TMZ resistance. Cx43 levels were inversely correlated with TMZ sensitivity of GBM cells, including GBM stem cells. Moreover, Cx43 levels inversely correlated with patient survival, including as observed in MGMT-deficient GBM patients. Addition of the C-terminal peptide mimetic αCT1, a selective inhibitor of Cx43 channels, sensitized human MGMT-deficient and TMZ-resistant GBM cells to TMZ treatment. Moreover, combining αCT1 with TMZ-blocked AKT/mTOR signaling, induced autophagy and apoptosis in TMZ-resistant GBM cells. Our findings suggest that Cx43 may offer a biomarker to predict the survival of patients with MGMT-independent TMZ resistance and that combining a Cx43 inhibitor with TMZ could enhance therapeutic responses in GBM, and perhaps other TMZ-resistant cancers.
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murphy
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Robin T
authors.initials: RT
authors.lastname: Varghese
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia. FirstString Research Inc., Mount Pleasant, South Carolina.
authors.forename: Samy
authors.initials: S
authors.lastname: Lamouille
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Guo
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pridham
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Pratik
authors.initials: P
authors.lastname: Kanabur
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Osimani
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Shaan
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Jane
authors.initials: J
authors.lastname: Jourdan
authors.affiliation: Department of Neurosurgery, Carilion Clinic, Roanoke, Virginia.
authors.forename: Cara M
authors.initials: CM
authors.lastname: Rodgers
authors.affiliation: Department of Neurosurgery, Carilion Clinic, Roanoke, Virginia.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Simonds
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia. Faculty of Health Science, Virginia Tech, Blacksburg, Virginia. Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, Virginia. Department of Emergency Medicine, Virginia Tech Carilion School of Medicine, Roanoke, Virginia. zhisheng@vtc.vt.edu gourdier@vtc.vt.edu.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gourdie
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, Virginia. Faculty of Health Science, Virginia Tech, Blacksburg, Virginia. Department of Biological Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia. Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, Virginia. zhisheng@vtc.vt.edu gourdier@vtc.vt.edu.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Sheng
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018031:Connexin 43; D010455:Peptides; D003606:Dacarbazine; D000077204:Temozolomide