Background/Objectives: Rho small GTPases (RSG), which regulates metastasis, constitute eight subfamilies—“classical” Rho, Rac, cdc42, and “atypical” Rif, Rnd, Wrch, RhoH, and RhoBTB. Their downstream signaling requires switching between GTP-bound active and GDP-bound inactive forms. Classical RSGs, but not atypical RSGs, require regulation by guanine nucleotide exchange factors (GEF), GTPase-activating proteins (GAP) and guanine nucleotide dissociation inhibitors (GDI) to achieve this switch. The objective of this review is to summarize the roles of RSGs in metastatic prostate cancer (mPCa) and their interaction with the androgen receptor (AR), which regulates this disease.Methods: We summarize the literature that describes the role of RSGs in mPCa, and their interaction with the AR.Results: Classical RSGs mostly promote metastasis (except RhoB), whereas atypical RSGs, with exceptions, mostly prevent it. Their role, however, is context-dependent—e.g., RhoB is tumor-suppressive in AR-null PCa but oncogenic in AR-positive tumors. The AR modulates RSG expression transcriptionally, but also affects their function through modulation of GEFs, GAPs, and GDIs. In turn, RSGs also regulate AR transcriptional activity. Interestingly, RSGs and the AR have non-genomic interactions via membrane-localized AR (mAR) not affected by AR inhibitors.Conclusions: Drugs that target RSGs are needed along with AR inhibitors to prevent mPCa progression.
背景/目的：Rho小GTP酶（RSG）作为调控肿瘤转移的关键分子，包含八个亚家族——"经典"亚家族（Rho、Rac、cdc42）与"非典型"亚家族（Rif、Rnd、Wrch、RhoH、RhoBTB）。其下游信号传导依赖于GTP结合活性态与GDP结合非活性态之间的转换。经典RSG需要通过鸟苷酸交换因子（GEF）、GTP酶激活蛋白（GAP）及鸟苷酸解离抑制因子（GDI）的调控实现状态转换，而非典型RSG则无需此类调控。本综述旨在系统阐述RSG在转移性前列腺癌（mPCa）中的作用及其与该疾病关键调控因子——雄激素受体（AR）的相互作用机制。 方法：通过系统梳理现有文献，总结RSG在mPCa中的功能及其与AR的相互作用关系。 结果：经典RSG（除RhoB外）主要促进肿瘤转移，而非典型RSG（存在例外情况）主要发挥抑制作用。值得注意的是，RSG的功能具有环境依赖性——例如RhoB在AR缺失型前列腺癌中表现为抑癌作用，而在AR阳性肿瘤中却呈现促癌特性。AR不仅通过转录调控影响RSG表达，还能通过调节GEF、GAP和GDI影响其功能。反之，RSG也能调控AR的转录活性。值得关注的是，RSG与AR可通过膜定位AR（mAR）发生非基因组相互作用，且该作用不受AR抑制剂影响。 结论：为有效抑制mPCa进展，需联合应用靶向RSG药物与AR抑制剂。
Rho Small GTPase Family in Androgen-Regulated Prostate Cancer Progression and Metastasis
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