Krämer, Alwin

Raab, Marc S.

Rebacz, Blanka

Cellular Oncology

Harvard University - DASH 

Induction of Spindle Multipolarityby Centrosomal Cluster InhibitionThe Harvard community has made thisarticle openly available.  Please share  howthis access benefits you. Your story mattersCitation Krämer, Alwin, Marc S. Raab, and Blanka Rebacz. 2008. “Inductionof Spindle Multipolarity by Centrosomal Cluster Inhibition.” CellularOncology : the Official Journal of the International Society forCellular Oncology 30 (6): 505-506. doi:10.3233/CLO-2008-0450.http://dx.doi.org/10.3233/CLO-2008-0450.Published Version doi:10.3233/CLO-2008-0450Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:24983929Terms of Use This article was downloaded from Harvard University’s DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACellular Oncology 30 (2008) 505–506 505DOI 10.3233/CLO-2008-0450IOS PressLetter to the EditorInduction of spindle multipolarity by centrosomal cluster inhibition ∗Sir,The centrosome is a small organelle which con-sists of two centrioles and a pericentriolar matrix [1].It functions as the microtubule-organizing center ofeukaryotic cells and plays a central role for the for-mation of the mitotic spindle. Supernumerary centro-somes have been described in almost all human ma-lignancies, including brain, breast, colon, lung, pan-creas, and prostate cancers as well as in leukemiasand lymphomas [2–4]. Furthermore, a striking corre-lation between centrosome aberrations and chromoso-mal instability as well as clinical aggressiveness hasbeen described for many tumor entities. Cells withsupernumerary centrosomes usually form multipolarspindles which lead to aberrant mitoses and conse-quently to chromosome miss-segregation. To regainsecondary karyotype stability after clonal selection, tu-mor cells coalesce their extra centrosomes by a poorlydefined mechanism into two spindle poles in order todivide properly and thus to survive [5]. Here, we de-scribe a screening procedure for the identification ofboth small molecules and siRNAs that inhibit centro-somal clustering and thus force tumor cells with super-numerary centrosomes to undergo multipolar mitosesand consequently apoptosis. For this purpose, squa-mous cell carcinoma cells which harbour extra copiesof centrosomes (SCC114) and nevertheless divide ina strictly bipolar fashion [5] are used as a model sys-tem and treated with either small molecules or a wholegenome siRNA library to investigate if they have aneffect on spindle polarity. Analysis is performed byhigh-throughput microscopy, using a SCC114 clonethat stably expresses GFP-α-tubulin. Using a genome-wide siRNA library resulted in the identification of∼150 proteins involved in the clustering of super-numerary centrosomes into a bipolar mitotic spindle.Screening of a small molecule library led to the identi-fication of several substances which are currently char-*This work was presented at the 2nd Conference on Aneuploidyand Cancer, Oakland, January 31–February 3, 2008.acterized in more detail. One of these substances is thewell-known antifungal drug griseofulvin, which led toan increased frequency of multipolar mitoses, mitoticarrest and apoptosis in several different tumor cell lineswhereas normal fibroblasts and keratinocytes were notaffected [6]. In addition, a griseofulvin derivative in-hibited in vivo tumor growth in a murine xenograftmodel of human colon cancer. The identification ofproteins that are components of the centrosomal clus-tering machinery in tumor cells will help to clarifythe mechanisms of how tumor cells coalesce super-numerary centrosomes into bipolar spindles. Further-more, this knowledge will enable us to determine spe-cific targets for anti-cancer therapy and thus for drugdevelopment.Alwin Krämera,∗∗, Marc S. Raabb andBlanka RebaczaaClinical Cooperation Unit MolecularHematology/Oncology,German Cancer Research Center and Departmentof Internal Medicine, University of Heidelberg,Heidelberg, GermanybDepartment of Medical Oncology, Dana-FarberCancer Institute, Harvard Medical School,Boston, MA, USA**Corresponding author: Alwin Krämer, Clinical CooperationUnit Molecular Hematology/Oncology, German Cancer ResearchCenter and Department of Internal Medicine, University of Hei-delberg, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.Tel.: +49 6221 421440; Fax: +49 6221 421444; E-mail: a.kraemer@dkfz.de.References[1] M. Bornens, Centrosome composition and microtubule anchor-ing mechanisms, Curr. Opin. Cell Biol. 14 (2002), 25–34.[2] E.A. Nigg, Centrosome aberrations: cause or consequence ofcancer progression?, Nat. Rev. Cancer 2 (2002), 815–825.1570-5870/08/$17.00© 2008 – IOS Press and the authors. All rights reserved506 Letter to the Editor[3] K. Neben, C. Giesecke, S. Schweizer, A.D. Ho and A. Krämer,Centrosome aberrations in acute myeloid leukemia are corre-lated with cytogenetic risk profile, Blood 101 (2003), 289–291.[4] A. Krämer, S. Schweizer, K. Neben, P. Lichter, U. Krause,C. Giesecke, J. Kalla, H.K. Müller-Hermelink, A.D. Ho andG. Ott, Centrosome aberrations as a possible mechanism forchromosomal instability in non-Hodgkin lymphomas, Leukemia17 (2003), 2207–2013.[5] N.J. Quintyne, J.E. Reing, D.R. Hoffelder, S.M. Gollin andW.S. Saunders, Spindle multipolarity is prevented by centroso-mal clustering, Science 307 (2005), 127–129.[6] B. Rebacz, T.O. Larsen, M. Clausen, M. Ronnest, H. Löffler,A.D. Ho and A. Krämer, Identification of griseofulvin as an in-hibitor of centrosomal clustering in a phenotype-based screen,Cancer Res. 67 (2007), 6342–6350.

Induction of Spindle Multipolarity by Centrosomal Cluster Inhibition

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Induction of Spindle Multipolarity by Centrosomal Cluster Inhibition

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