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@ARTICLE{Konotop:128941,
      author       = {G. Konotop$^*$ and E. Bausch$^*$ and T. Nagai and A.
                      Turchinovich$^*$ and N. Becker$^*$ and A. Benner$^*$ and M.
                      Boutros$^*$ and K. Mizuno and A. Krämer$^*$ and M.-S.
                      Raab$^*$},
      title        = {{P}harmacological {I}nhibition of {C}entrosome {C}lustering
                      by {S}lingshot-{M}ediated {C}ofilin {A}ctivation and {A}ctin
                      {C}ortex {D}estabilization.},
      journal      = {Cancer research},
      volume       = {76},
      number       = {22},
      issn         = {1538-7445},
      address      = {Philadelphia, Pa.},
      publisher    = {AACR},
      reportid     = {DKFZ-2017-04953},
      pages        = {6690 - 6700},
      year         = {2016},
      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.},
      keywords     = {Actins (NLM Chemicals) / Cofilin 1 (NLM Chemicals)},
      cin          = {G170 / C080 / C060 / B110 / G330},
      ddc          = {610},
      cid          = {I:(DE-He78)G170-20160331 / I:(DE-He78)C080-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)B110-20160331 /
                      I:(DE-He78)G330-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27634760},
      doi          = {10.1158/0008-5472.CAN-16-1144},
      url          = {https://inrepo02.dkfz.de/record/128941},
}