SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide.
SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide.
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DOI：
10.1158/1541-7786.mcr-15-0183
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Tran NL
中科院分区：
文献类型：
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作者：
Ensign SP;Roos A;Mathews IT;Dhruv HD;Tuncali S;Sarkaria JN;Symons MH;Loftus JC;Berens ME;Tran NL
胶质母细胞瘤（GB）是原发性成人脑肿瘤的最高级别和最常见的形式。尽管手术切除后同时进行放疗和烷化剂替莫唑胺 (TMZ) 化疗，GB 肿瘤仍会出现治疗耐药性并最终复发。对治疗的反应迅速受损，中位生存期仅为十五个月。因此，有必要确定促进肿瘤抵抗的遗传和信号传导机制，以便开发靶向疗法来对抗这种难治性疾病。先前的观察表明，SGEF (ARHGEF26) 是一种 RhoG 特异性鸟嘌呤核苷酸交换因子 (GEF)，在 GB 肿瘤中过度表达，并在促进 TWEAK-Fn14 介导的神经胶质瘤侵袭中发挥作用。在这里，进一步的研究揭示了 SGEF 在神经胶质瘤细胞存活中的重要作用。 SGEF 表达通过 NF-κB 活性通过 TWEAK-Fn14 信号传导上调，而 shRNA 介导的 SGEF 表达减少使神经胶质瘤细胞对 TMZ 诱导的细胞凋亡敏感，并抑制 TMZ 治疗后集落形成。核 SGEF 在 TMZ 暴露后被激活，并与 DNA 损伤修复 (DDR) 蛋白 BRCA1 形成复合物。此外，响应 TMZ 治疗的 BRCA1 磷酸化受到 SGEF 敲低的阻碍。 SGEF 在促进化疗耐药方面的作用凸显了一个迄今为止未被认识的驱动因素，并表明其有可能成为开发针对 TMZ 难治性、侵袭性 GB 细胞的新型靶向疗法的候选药物。 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。
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 (TMZ), 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 in order 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 up-regulated by TWEAK-Fn14 signaling via NF-κB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to TMZ-induced apoptosis and suppresses colony formation following TMZ treatment. Nuclear SGEF is activated following TMZ exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to TMZ 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 TMZ refractory, invasive GB cells. SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma.