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The Rho GTPase signalling pathway in urothelial carcinoma

Nature Reviews Urology volume 15, pages 83–91 (2018)Cite this article

Subjects

Key Points

  • The Rho GTPase family of enzymes is a diverse group of proteins that have critical roles in a number of cellular processes, including cell migration, cell polarity, cell adhesion, cell cycle progression, and regulation of the cytoskeleton. At present, transforming protein RhoA, Ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division control protein 42 homologue (CDC42) are the best characterized

  • The processes that involve Rho GTPases are integral to the development, progression, and spread of malignancy, including urothelial carcinoma

  • The activity of these GTPases is regulated by a number of regulatory proteins, including guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and, in certain classes of GTPases, guanine nucleotide exchange inhibitors (GDIs)

  • The growing understanding of Rho GTPase pathway regulation has resulted in identification of many potential drug targets in several cancers, including urothelial carcinoma. The most promising drug targets are those that inhibit Rho-associated protein kinase (ROCK), a downstream effector of RhoA

  • Most studies of the relationships between the Rho GTPase pathway and malignancy are being performed in preclinical models; the cell culture studies show promise, suggesting that activity levels of proteins are linked with disease characteristics and that inhibition of these proteins can have favourable effects on the disease phenotype

  • In vitro studies are promising, but this field is nascent and it remains to be seen whether manipulation of the Rho GTPase pathway can be a clinically useful anticancer tool. Rho GTPases are highly conserved proteins with considerable homology and complex regulatory processes, meaning considerable potential for off-target effects exists

Abstract

Urothelial carcinoma remains a clinical challenge: non-muscle-invasive disease has a high rate of recurrence and risk of progression, and outcomes for patients with advanced disease are poor, owing to a lack of effective systemic therapies. The Rho GTPase family of enzymes was first identified >30 years ago and contains >20 members, which are divided into eight subfamilies: Cdc42, Rac, Rho, RhoUV, RhoBTB, RhoDF, RhoH, and Rnd. Rho GTPases are molecular on–off switches, which are increasingly being understood to have a critical role in a number of cellular processes, including cell migration, cell polarity, cell adhesion, cell cycle progression, and regulation of the cytoskeleton. This switch is an evolutionarily conserved system in which GTPases alternate between GDP-bound (inactive) and GTP-bound (active) forms. The activities of these Rho GTPases are many, context-dependent, and regulated by a number of proteins that are being progressively elucidated. Aberrations of the Rho GTPase signalling pathways have been implicated in various malignancies, including urothelial carcinoma, and understanding of the role of Rho GTPases in these diseases is increasing. This signalling pathway has the potential for therapeutic targeting in urothelial carcinoma. Research in this area is nascent, and much work is necessary before current laboratory-based research can be translated into the clinic.

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Figure 1: Types and stages of bladder cancer.
Figure 2: The Rho GTPase molecular switch and its regulators.
Figure 3: The Rho GTPase family.
Figure 4: Function of Rho-associated protein kinases (ROCKs).

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Author notes

  1. Solomon L. Woldu and Ryan C. Hutchinson: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390–9110, Texas, USA

    Solomon L. Woldu, Ryan C. Hutchinson, Laura-Maria Krabbe, Oner Sanli & Vitaly Margulis

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  1. Solomon L. Woldu
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  2. Ryan C. Hutchinson
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  3. Laura-Maria Krabbe
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Contributions

S.L.W., R.C.H., and L.-M.K. researched data for the article; S.L.W., R.C.H., O.S., and V.M. made substantial contributions to discussions of content; S.L.W. and R.C.H. wrote the article; and S.L.W., L.-M.K., O.S., and V.M. reviewed and edited the manuscript before submission.

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Correspondence to Vitaly Margulis.

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Woldu, S., Hutchinson, R., Krabbe, LM. et al. The Rho GTPase signalling pathway in urothelial carcinoma. Nat Rev Urol 15, 83–91 (2018). https://doi.org/10.1038/nrurol.2017.184

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