title: SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide.
abstract: Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide, GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG-specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and plays a role in promoting TWEAK-Fn14-mediated glioma invasion. Here, further investigation revealed an important role for SGEF in glioma cell survival. SGEF expression is upregulated by TWEAK-Fn14 signaling via NF-κB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to temozolomide-induced apoptosis and suppresses colony formation following temozolomide treatment. Nuclear SGEF is activated following temozolomide exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to temozolomide treatment is hindered by SGEF knockdown. The role of SGEF in promoting chemotherapeutic resistance highlights a heretofore unappreciated driver, and suggests its candidacy for development of novel targeted therapeutics for temozolomide-refractory, invasive GB cells.
  
  
  CONCLUSIONS
  SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma.
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona. Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona.
authors.forename: Shannon P Fortin
authors.initials: SP
authors.lastname: Ensign
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Alison
authors.initials: A
authors.lastname: Roos
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Mathews
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Harshil D
authors.initials: HD
authors.lastname: Dhruv
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Serdar
authors.initials: S
authors.lastname: Tuncali
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, New York.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Symons
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona. ntran@tgen.org.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000074049:Cytokine TWEAK; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000074050:TWEAK Receptor; D000077204:Temozolomide; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C473930:ARHGEF26 protein, human; D018906:Antineoplastic Agents, Alkylating; D000074049:Cytokine TWEAK; D020662:Guanine Nucleotide Exchange Factors; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D003606:Dacarbazine; D000077204:Temozolomide