Ensign Shannon P Fortin, Roos Alison, Mathews Ian T, Dhruv Harshil D, Tuncali Serdar, Sarkaria Jann N, Symons Marc H, Loftus Joseph C, Berens Michael E, Tran Nhan L
Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona. Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona.
Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
Mol Cancer Res. 2016 Mar;14(3):302-12. doi: 10.1158/1541-7786.MCR-15-0183. Epub 2016 Jan 13.
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.
SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma.
胶质母细胞瘤（GB）是成人原发性脑肿瘤中分级最高且最常见的形式。尽管进行了手术切除，随后联合使用烷化剂替莫唑胺进行放疗和化疗，但GB肿瘤仍会产生治疗抗性并最终复发。对治疗的反应受损迅速出现，导致中位生存期仅为15个月。因此，有必要确定促进肿瘤抗性的遗传和信号传导机制，以开发针对性疗法来对抗这种难治性疾病。先前的观察表明，RhoG特异性鸟嘌呤核苷酸交换因子（GEF）SGEF（ARHGEF26）在GB肿瘤中过表达，并在促进TWEAK-Fn14介导的胶质瘤侵袭中起作用。在这里，进一步的研究揭示了SGEF在胶质瘤细胞存活中的重要作用。SGEF表达通过TWEAK-Fn14信号通过NF-κB活性上调，而shRNA介导的SGEF表达降低使胶质瘤细胞对替莫唑胺诱导的凋亡敏感，并抑制替莫唑胺治疗后的集落形成。替莫唑胺暴露后，核SGEF被激活，并与DNA损伤修复（DDR）蛋白BRCA1形成复合物。此外，SGEF敲低阻碍了替莫唑胺治疗后BRCA1的磷酸化。SGEF在促进化疗抗性中的作用突出了一个迄今未被认识的驱动因素，并表明它有资格成为开发针对替莫唑胺难治性、侵袭性GB细胞的新型靶向疗法的候选者。
SGEF作为细胞存活和侵袭的双重过程调节剂，代表了治疗难治性胶质母细胞瘤的新靶点。
