# Rho Small GTPase Family in Androgen-Regulated Prostate Cancer Progression and Metastasis

## TL;DR

This paper reviews how Rho GTPases interact with androgen receptors to influence prostate cancer progression and metastasis.

## Contribution

The paper systematically reviews the role of Rho small GTPases in metastatic prostate cancer and their interaction with the androgen receptor.

## Key findings

- Classical RSGs mostly promote metastasis, while atypical RSGs mostly prevent it, with exceptions.
- RhoB acts as a tumor suppressor in AR-null PCa but as an oncogene in AR-positive tumors.
- RSGs and AR have non-genomic interactions via membrane-localized AR unaffected by AR inhibitors.

## Abstract

While local and regional prostate cancer (PCa) maintains a nearly 100% 5-year overall survival, metastatic PCa (mPCa) reduces 5-year overall survival to 38%. Since PCa is strongly regulated by the androgen receptor (AR), initial treatment for mPCa involves drugs that inhibit the AR pathway. However, resistance to these treatments eventually ensue, resulting in castration-resistant PCa (CRPC). Understanding the biology behind mPCa progression is therefore necessary to identify additional treatments that may prevent this progression. One of the most studied pathways that regulate metastasis is the 20-member Rho small GTPase (RSG) family that regulate migration and invasion and activate downstream targets by switching from a guanosine triphosphate (GTP)-bound active form into a guanosine diphosphate (GDP)-bound inactive form. In this systematic review, we explore the role of the Rho GTPases in mPCa and the interaction between classical Rho GTPases with the AR that regulates the progression of this disease.

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.