SMIFH2 has effects on Formins and p53 that perturb the cell cytoskeleton.
Formin proteins are key regulators of the cytoskeleton involved in developmental and homeostatic programs, and human disease. For these reasons, small molecules interfering with Formins' activity have gained increasing attention. Among them, small molecule inhibitor of Formin Homology 2 domains (SMIFH2) is often used as a pharmacological Formin blocker. Although SMIFH2 inhibits actin polymerization by Formins and affects the actin cytoskeleton, its cellular mechanism of action and target specificity remain unclear. Here we show that SMIFH2 induces remodelling of actin filaments, microtubules and the Golgi complex as a result of its effects on Formins and p53. We found that SMIFH2 triggers alternated depolymerization-repolymerization cycles of actin and tubulin, increases cell migration, causes scattering of the Golgi complex, and also cytotoxicity at high dose. Moreover, SMIFH2 reduces expression and activity of p53 through a post-transcriptional, proteasome-independent mechanism that influences remodelling of the cytoskeleton. As the action of SMIFH2 may go beyond Formin inhibition, only short-term and low-dose SMIFH2 treatments minimize confounding effects induced by loss of p53 and cytotoxicity.
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Tadamoto
T
Isogai
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Rob
R
van der Kammen
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Metello
M
Innocenti
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D000199:Actins; D008840:Microfilament Proteins; C547376:SMIFH2 compound; D054852:Small Molecule Libraries; C495901:TP53 protein, human; D013871:Thiones; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D014498:Uracil; D046988:Proteasome Endopeptidase Complex