Small-molecule agonists of mammalian Diaphanous-related (mDia) formins reveal an effective glioblastoma anti-invasion strategy.
Small-molecule agonists of mammalian Diaphanous-related (mDia) formins reveal an effective glioblastoma anti-invasion strategy.
复制标题
哺乳动物透射相关（MDIA）formins的小分子激动剂揭示了有效的胶质母细胞瘤抗染色策略。
DOI：
10.1091/mbc.e14-11-1502
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发表时间：
2015-11-01
影响因子：
3.3
通讯作者：
Eisenmann KM
中科院分区：
文献类型：
--
作者：
Arden JD;Lavik KI;Rubinic KA;Chiaia N;Khuder SA;Howard MJ;Nestor-Kalinoski AL;Alberts AS;Eisenmann KM
Formin agonists impede the most dangerous aspect of glioblastoma—tumor spread into surrounding healthy tissue. Formin activation impairs a novel aspect of the transformed cell and informs the development of antitumor strategies for a cancer needing a more effective therapy. The extensive invasive capacity of glioblastoma (GBM) makes it resistant to surgery, radiotherapy, and chemotherapy and thus makes it lethal. In vivo, GBM invasion is mediated by Rho GTPases through unidentified downstream effectors. Mammalian Diaphanous (mDia) family formins are Rho-directed effectors that regulate the F-actin cytoskeleton to support tumor cell motility. Historically, anti-invasion strategies focused upon mDia inhibition, whereas activation remained unexplored. The recent development of small molecules directly inhibiting or activating mDia-driven F-actin assembly that supports motility allows for exploration of their role in GBM. We used the formin inhibitor SMIFH2 and mDia agonists IMM-01/-02 and mDia2-DAD peptides, which disrupt autoinhibition, to examine the roles of mDia inactivation versus activation in GBM cell migration and invasion in vitro and in an ex vivo brain slice invasion model. Inhibiting mDia suppressed directional migration and spheroid invasion while preserving intrinsic random migration. mDia agonism abrogated both random intrinsic and directional migration and halted U87 spheroid invasion in ex vivo brain slices. Thus mDia agonism is a superior GBM anti-invasion strategy. We conclude that formin agonism impedes the most dangerous GBM component—tumor spread into surrounding healthy tissue. Formin activation impairs novel aspects of transformed cells and informs the development of anti-GBM invasion strategies.
