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

Autor: Kyriazi D; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Voth L; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Bader A; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Ewert W; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.; Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany., Gerlach J; Faculty of Chemistry, TU Dresden, Dresden, Germany., Elfrink K; Institute of Integrative Cell Biology and Physiology, University of Münster, Münster, Germany., Franz P; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Tsap MI; Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany., Schirmer B; Institute of Pharmacology, Hannover Medical School, Hannover, Germany., Damiano-Guercio J; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Hartmann FK; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Plenge M; Department of Cell Physiology and Biophysics, Institute of Cell Biology and Biophysics, Leibniz Universität Hannover, Hannover, Germany., Salari A; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany., Schöttelndreier D; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Strienke K; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Bresch N; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Salinas C; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Gutzeit HO; Department of Biology, TU Dresden, Dresden, Germany., Schaumann N; Institute for Pathology, Hannover Medical School, Hannover, Germany., Hussein K; Institute of Pathology, KRH Klinikum Nordstadt, Hannover, Germany., Bähre H; Research Core Unit Mass Spectrometry-Metabolomics, Hannover Medical School, Hanover, Germany., Brüsch I; Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany., Claus P; SMATHERIA gGmbH-Non-Profit Biomedical Research Institute, Hannover, Germany., Neumann D; Institute of Pharmacology, Hannover Medical School, Hannover, Germany., Taft MH; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany., Shcherbata HR; Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany., Ngezahayo A; Department of Cell Physiology and Biophysics, Institute of Cell Biology and Biophysics, Leibniz Universität Hannover, Hannover, Germany., Bähler M; Institute of Integrative Cell Biology and Physiology, University of Münster, Münster, Germany., Amiri M; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany., Knölker HJ; Faculty of Chemistry, TU Dresden, Dresden, Germany., Preller M; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.; Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany., Tsiavaliaris G; Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany. Tsiavaliaris.Georgios@mh-hannover.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 16; Vol. 15 (1), pp. 9947. Date of Electronic Publication: 2024 Nov 16.
DOI: 10.1038/s41467-024-54181-6
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.
Competing Interests: Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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