title: Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43.
abstract: Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM.
authors.affiliation: 1] Rutgers-Graduate School of Biomedical Science, Newark, NJ, USA [2] Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Munoz
authors.affiliation: Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA.
authors.forename: V
authors.initials: V
authors.lastname: Rodriguez-Cruz
authors.affiliation: Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Greco
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Ramkissoon
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA.
authors.forename: P
authors.initials: P
authors.lastname: Rameshwar
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D004396:Coloring Agents; D018031:Connexin 43; D018808:Transcription Factor AP-1; D003606:Dacarbazine; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000077204:Temozolomide