TY  - JOUR
U1  - Wissenschaftlicher Artikel
A1  - Kyriazi, Despoina
A1  - Voth, Lea
A1  - Bader, Almke
A1  - Ewert, Wiebke
A1  - Gerlach, Juliane
A1  - Elfrink, Kerstin
A1  - Franz, Peter
A1  - Tsap, Mariana I.
A1  - Schirmer, Bastian
A1  - Damiano-Guercio, Julia
A1  - Hartmann, Falk K.
A1  - Plenge, Masina
A1  - Salari, Azam
A1  - Schöttelndreier, Dennis
A1  - Strienke, Katharina
A1  - Bresch, Nadine
A1  - Salinas, Claudio
A1  - Gutzeit, Herwig O.
A1  - Schaumann, Nora
A1  - Hussein, Kais
A1  - Bähre, Heike
A1  - Brüsch, Inga
A1  - Claus, Peter
A1  - Neumann, Detlef
A1  - Taft, Manuel H.
A1  - Shcherbata, Halyna R.
A1  - Ngezahayo, Anaclet
A1  - Bähler, Martin
A1  - Amiri, Mahdi
A1  - Knölker, Hans-Joachim
A1  - Preller, Matthias
A1  - Tsiavaliaris, Georgios
T1  - An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells
JF  - Nature Communications
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.
Y1  - 2024
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-87388
SN  - 2041-1723
SS  - 2041-1723
U6  - https://doi.org/10.1038/s41467-024-54181-6
DO  - https://doi.org/10.1038/s41467-024-54181-6
PM  - 39550360
VL  - 15
SP  - 25
S1  - 25
PB  - Springer Nature
ER  -