Cancer Therapeutics Program, Ottawa Hospital Research Institute , Ottawa, Canada.
Department of Medicine, University of Ottawa , Ottawa, Ontario, Canada.
Small GTPases. 2021 Mar;12(2):81-95. doi: 10.1080/21541248.2019.1612694. Epub 2019 May 6.
Glioblastoma is an aggressive and incurable form of brain cancer. Both mutation analysis in human glioblastoma and mouse modelling studies have shown that aberrant activation of the PI 3-kinase pathway is a central driver of glioblastoma malignancy. The small GTPase Rac is activated downstream of this pathway, mediating a subset of the effects of aberrant PI 3-kinase pathway activation. Here I discuss the current state of our knowledge on Rac activation mechanisms in glioblastoma. Current knowledge on roles for specific PI 3-kinase pathway responsive Rac guanine nucleotide exchange factors in glioblastoma is reviewed. Rac is best known for its role in promoting cell motility and invasion, but there is also evidence for roles in multiple other cellular processes with cancer relevance, including proliferation, differentiation, apoptosis, DNA damage responses, metabolism, angiogenesis and immunosuppression. I review what is known about the role of Rac in these processes in glioblastoma. Finally, I assess possible strategies to inhibit this pathway in glioblastoma through either direct inhibition of Rac or inhibition of upstream activators or downstream mediators of Rac signalling.
胶质母细胞瘤是一种侵袭性和无法治愈的脑癌。人类胶质母细胞瘤的突变分析和小鼠模型研究都表明，PI3 激酶通路的异常激活是胶质母细胞瘤恶性的核心驱动因素。小 GTPase Rac 是该通路的下游激活物，介导异常 PI3 激酶通路激活的一部分作用。在这里，我讨论了我们目前对胶质母细胞瘤中 Rac 激活机制的了解。本文综述了特定的 PI3 激酶通路反应性 Rac 鸟嘌呤核苷酸交换因子在胶质母细胞瘤中的作用的现有知识。Rac 最著名的作用是促进细胞运动和侵袭，但也有证据表明它在其他与癌症相关的多个细胞过程中发挥作用，包括增殖、分化、凋亡、DNA 损伤反应、代谢、血管生成和免疫抑制。我综述了 Rac 在这些过程中在胶质母细胞瘤中的作用。最后，我评估了通过直接抑制 Rac 或抑制 Rac 信号的上游激活剂或下游介质来抑制该通路在胶质母细胞瘤中的可能策略。
