SGEF is regulated via TWEAK/Fn14/NF-κB signaling and promotes survival by modulation of the DNA repair response to temozolomide

Shannon P. Fortin Ensign, Alison Roos, Ian T. Mathews, Harshil D. Dhruv, Serdar Tuncali, Jann N Sarkaria, Marc H. Symons, Joseph C Loftus, Michael E. Berens, Nhan Tran

Research output: Contribution to journalArticle

9 Scopus citations

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. Implication: SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma.

Original languageEnglish (US)
Pages (from-to)302-312
Number of pages11
JournalMolecular Cancer Research
Volume14
Issue number3
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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