An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the ide...

Full description

Saved in:

Bibliographic Details
Published in:	Nature communications Vol. 15; no. 1; pp. 9947 - 25
Main Authors:	Kyriazi, Despoina, Voth, Lea, Bader, Almke, Ewert, Wiebke, Gerlach, Juliane, Elfrink, Kerstin, Franz, Peter, Tsap, Mariana I., Schirmer, Bastian, Damiano-Guercio, Julia, Hartmann, Falk K., Plenge, Masina, Salari, Azam, Schöttelndreier, Dennis, Strienke, Katharina, Bresch, Nadine, Salinas, Claudio, Gutzeit, Herwig O., Schaumann, Nora, Hussein, Kais, Bähre, Heike, Brüsch, Inga, Claus, Peter, Neumann, Detlef, Taft, Manuel H., Shcherbata, Halyna R., Ngezahayo, Anaclet, Bähler, Martin, Amiri, Mahdi, Knölker, Hans-Joachim, Preller, Matthias, Tsiavaliaris, Georgios
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-11-2024 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/106 13/109 13/31 13/51 13/89 14/19 631/154/556 631/45/535/1266 631/80/128/1675 631/80/84/2027 631/80/86/2341 64/24 64/60 82/58 82/83 Actin Actomyosin Adenocarcinoma Allosteric properties Animal models Cancer Cancer therapies Carbazole Carbazoles Cell culture Cell migration Contractility Cytokinesis Human motion Humanities and Social Sciences Inhibitors Melanoma Metastases Metastasis multidisciplinary Myosin Organoids Rho-associated kinase RhoA protein Science Science (multidisciplinary)
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies. This study reports adhibin, a synthetic carbazole that suppresses the migratory and adhesive properties of cancer cells by a mechanism of targeted RhoGAP class-IX myosin inhibition and selective RhoGTPase interference, both translating into migrastatic activity, opening other perspectives in cancer therapy and basic research.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-54181-6