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

Autor: 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
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Zdroj: Nature Communications; 11/16/2024, Vol. 15 Issue 1, p1-25, 25p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
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