The Rac GTPase in Cancer: From Old Concepts to New Paradigms.
The Rac GTPase in Cancer: From Old Concepts to New Paradigms.
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DOI：
10.1158/0008-5472.can-17-1456
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发表时间：
2017-10-15
期刊：
影响因子：
11.2
通讯作者：
Caloca MJ
中科院分区：
文献类型：
--
作者：
Kazanietz MG;Caloca MJ
Rho 家族 GTP 酶是细胞功能的关键调节因子，在癌症进展中发挥重要作用。 Rho 小 G 蛋白（特别是 Rac1 及其调节因子）的异常活性是癌症的标志，并导致癌细胞的致瘤和转移表型。这篇综述探讨了导致 Rac1 过度激活的多种机制，特别关注涉及 Rac 和鸟嘌呤核苷酸交换因子 (GEF) 功能获得性突变、Rac1 降解缺陷以及 Rac 信号成分错误定位的新兴范例。 Rac GTP 酶激活蛋白 (GAP) 意想不到的促癌功能也挑战了这些负性 Rac 调节因子仅充当肿瘤抑制因子的教条。 Rac 过度激活对抗癌药物耐药性（包括靶向治疗）以及抑制抗肿瘤免疫反应的潜在贡献，凸显了在临床环境中开发针对 Rac 通路的治疗策略的迫切需要。
Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.