title: FGF-2 disrupts mitotic stability in prostate cancer through the intracellular trafficking protein CEP57.
abstract: Malignant tumors with deregulated FGF-2 expression such as prostate cancer are also frequently aneuploid. Aneuploidy can be caused by cell division errors due to extra centrosomes and mitotic spindle poles. However, a link between FGF-2 overexpression and chromosome missegregation has so far been elusive. Here, we show that FGF-2 rapidly uncouples centrosome duplication from the cell division cycle in prostate cancer cells through CEP57, an intracellular FGF-2-binding and trafficking factor. CEP57 was initially identified as a regulator of centriole overduplication in an RNA interference screen. We subsequently found that CEP57 rapidly stimulates centriole overduplication and mitotic defects when overexpressed and is required not only for FGF-2-induced centriole overduplication but also for normal centriole duplication. We provide evidence that CEP57 functions by modulating tubulin acetylation, thereby promoting daughter centriole stability. CEP57 was found to be overexpressed on the mRNA and protein level in a subset of prostate cancers, of which the vast majority also showed FGF-2 upregulation. Taken together, our results show an unexpected link between altered microenvironmental signaling cues such as FGF-2 overexpression and mitotic instability and provide a rationale for the therapeutic targeting of the FGF-2/FGFR1/CEP57 axis in prostate cancer. Cancer Res; 73(4); 1400-10. ©2012 AACR.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Rolando
authors.initials: R
authors.lastname: Cuevas
authors.forename: Nina
authors.initials: N
authors.lastname: Korzeniewski
authors.forename: Yanis
authors.initials: Y
authors.lastname: Tolstov
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002502:Centrioles / Q000187:drug effects / Q000378:metabolism; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
chemical_list: C474610:CEP57 protein, human; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014404:Tubulin; D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1