title: Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization.
abstract: Centrosome amplification is a hallmark of virtually all types of cancers, including solid tumors and hematologic malignancies. Cancer cells with extra centrosomes use centrosome clustering (CC) to allow for successful division. Because normal cells do not rely on this mechanism, CC is regarded as a promising target to selectively eradicate cells harboring supernumerary centrosomes. To identify novel inhibitors of CC, we developed a cell-based high-throughput screen that reports differential drug cytotoxicity for isogenic cell populations with different centrosome contents. We identified CP-673451 and crenolanib, two chemically related compounds originally developed for the inhibition of platelet-derived growth factor receptor β (PDGFR-β), as robust inhibitors of CC with selective cytotoxicity for cells with extra centrosomes. We demonstrate that these compounds induce mitotic spindle multipolarity by activation of the actin-severing protein cofilin, leading to destabilization of the cortical actin network, and provide evidence that this activation is dependent on slingshot phosphatases 1 and 2 but unrelated to PDGFR-β inhibition. More specifically, we found that although both compounds attenuated PDGF-BB-induced signaling, they significantly enhanced the phosphorylation of PDGFR-β downstream effectors, Akt and MEK, in almost all tested cancer cell lines under physiologic conditions. In summary, our data reveal a novel mechanism of CC inhibition depending on cofilin-mediated cortical actin destabilization and identify two clinically relevant compounds interfering with this tumor cell-specific target. Cancer Res; 76(22); 6690-700. ©2016 AACR.
authors.affiliation: Max-Eder Research Group "Experimental Therapies for Hematologic Malignancies", German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gleb
authors.initials: G
authors.lastname: Konotop
authors.affiliation: Max-Eder Research Group "Experimental Therapies for Hematologic Malignancies", German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Bausch
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Turchinovich
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Becker
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Division of Signaling and Functional Genomics, Medical Faculty Mannheim, German Cancer Research Center and University of Heidelberg, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. a.kraemer@dkfz.de.
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.affiliation: Max-Eder Research Group "Experimental Therapies for Hematologic Malignancies", German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marc Steffen
authors.initials: MS
authors.lastname: Raab
mesh_terms: D000199:Actins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism*; D051338:Cofilin 1 / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction
chemical_list: D000199:Actins; D051338:Cofilin 1