Details
| Original language | English |
|---|---|
| Article number | 9947 |
| Number of pages | 25 |
| Journal | Nature Communications |
| Volume | 15 |
| Issue number | 1 |
| Publication status | Published - 16 Nov 2024 |
Abstract
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.
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
- Biochemistry, Genetics and Molecular Biology(all)
- General Biochemistry,Genetics and Molecular Biology
- Physics and Astronomy(all)
- General Physics and Astronomy
Sustainable Development Goals
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In: Nature Communications, Vol. 15, No. 1, 9947, 16.11.2024.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells
AU - Kyriazi, Despoina
AU - Voth, Lea
AU - Bader, Almke
AU - Ewert, Wiebke
AU - Gerlach, Juliane
AU - Elfrink, Kerstin
AU - Franz, Peter
AU - Tsap, Mariana I.
AU - Schirmer, Bastian
AU - Damiano-Guercio, Julia
AU - Hartmann, Falk K.
AU - Plenge, Masina
AU - Salari, Azam
AU - Schöttelndreier, Dennis
AU - Strienke, Katharina
AU - Bresch, Nadine
AU - Salinas, Claudio
AU - Gutzeit, Herwig O.
AU - Schaumann, Nora
AU - Hussein, Kais
AU - Bähre, Heike
AU - Brüsch, Inga
AU - Claus, Peter
AU - Neumann, Detlef
AU - Taft, Manuel H.
AU - Shcherbata, Halyna R.
AU - Ngezahayo, Anaclet
AU - Bähler, Martin
AU - Amiri, Mahdi
AU - Knölker, Hans Joachim
AU - Preller, Matthias
AU - Tsiavaliaris, Georgios
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024/11/16
Y1 - 2024/11/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85209347234&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-54181-6
DO - 10.1038/s41467-024-54181-6
M3 - Article
C2 - 39550360
AN - SCOPUS:85209347234
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 9947
ER -