Home LiteratureArticle Details
PMID: 18662975 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes.

Genes & development ·Vol. 22 ·No. 16 ·2008-08-15 ·Pages 2189-203

Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M, Pellman D

Abstract

Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. A genome-wide RNAi screen in Drosophila S2 cells and a secondary analysis in cancer cells defined mechanisms that suppress multipolar mitoses. In addition to proteins that organize microtubules at the spindle poles, we identified novel roles for the spindle assembly checkpoint, cortical actin cytoskeleton, and cell adhesion. Using live cell imaging and fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. These findings may identify cancer-selective therapeutic targets: HSET, a normally nonessential kinesin motor, was essential for the viability of certain extra centrosome-containing cancer cells. Thus, morphological features of cancer cells can be linked to unique genetic requirements for survival.

MeSH Terms
Actins/metabolism Animals Cell Adhesion/physiology Cell Division Cell Line Cell Polarity Cell Shape Centrosome/metabolism Cytoskeleton/physiology Drosophila Proteins/genetics,metabolism Drosophila melanogaster/cytology,genetics Genome Interphase/physiology Kinesins/metabolism Microscopy, Fluorescence Microtubules/metabolism Mitosis Neoplasms/genetics,pathology Phenotype RNA, Small Interfering/pharmacology Spindle Apparatus
Chemicals
Actins Drosophila Proteins RNA, Small Interfering Kinesins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Kwon Mijung
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Godinho Susana A
Chandhok Namrata S
Ganem Neil J
Azioune Ammar
Thery Manuel
Pellman David
References (60)
60 references, click to expand
  1. Managing the centrosome numbers game: from chaos to stability in cancer cell division.
    Trends Cell Biol. 2001 Jan;11(1):18-21 PMID: 11146294
  2. Cell shape and cell division.
    Curr Opin Cell Biol. 2006 Dec;18(6):648-57 PMID: 17046223
  3. Oncogenic pathway signatures in human cancers as a guide to targeted therapies.
    Nature. 2006 Jan 19;439(7074):353-7 PMID: 16273092
  4. Oncogenes and tumour suppressors take on centrosomes.
    Nat Rev Cancer. 2007 Dec;7(12):911-24 PMID: 18004399
  5. Altered centrosome structure is associated with abnormal mitoses in human breast tumors.
    Am J Pathol. 1999 Dec;155(6):1941-51 PMID: 10595924
  6. Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation.
    Cell. 2003 Apr 4;113(1):37-47 PMID: 12679033
  7. The mitotic spindle: a self-made machine.
    Science. 2001 Oct 19;294(5542):543-7 PMID: 11641489
  8. Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function.
    Nat Cell Biol. 2005 Nov;7(11):1133-9 PMID: 16244666
  9. Mitosis in a cell with multiple centrioles.
    J Cell Biol. 1982 Sep;94(3):549-56 PMID: 7130271
  10. The extracellular matrix guides the orientation of the cell division axis.
    Nat Cell Biol. 2005 Oct;7(10):947-53 PMID: 16179950
  11. INF2 Is a WASP homology 2 motif-containing formin that severs actin filaments and accelerates both polymerization and depolymerization.
    J Biol Chem. 2006 Sep 8;281(36):26754-67 PMID: 16818491
  12. Re-evaluating centrosome function.
    Nat Rev Mol Cell Biol. 2001 Sep;2(9):688-98 PMID: 11533726
  13. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen.
    Science. 1999 Oct 29;286(5441):971-4 PMID: 10542155
  14. Differential mitotic responses to microtubule-stabilizing and -destabilizing drugs.
    Cancer Res. 2002 Apr 1;62(7):1935-8 PMID: 11929805
  15. Microtubules suppress actomyosin-based cortical flow in Xenopus oocytes.
    J Cell Sci. 1997 Aug;110 ( Pt 16):1907-17 PMID: 9296390
  16. Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas.
    Cancer Res. 2003 Mar 15;63(6):1398-404 PMID: 12649205
  17. Inscuteable-dependent apical localization of the microtubule-binding protein Cornetto suggests a role in asymmetric cell division.
    J Cell Sci. 2001 Oct;114(Pt 20):3655-62 PMID: 11707517
  18. Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity.
    Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2950-5 PMID: 9501196
  19. Assembly and dynamics of an anastral:astral spindle: the meiosis II spindle of Drosophila oocytes.
    J Cell Sci. 1998 Sep;111 ( Pt 17):2487-95 PMID: 9701548
  20. Actin based motility on retraction fibers in mitotic PtK2 cells.
    Cell Motil Cytoskeleton. 1992;22(2):135-51 PMID: 1633624
  21. A functional genomic analysis of cell morphology using RNA interference.
    J Biol. 2003;2(4):27 PMID: 14527345
  22. Terminal cytokinesis events uncovered after an RNAi screen.
    Curr Biol. 2004 Sep 21;14(18):1685-93 PMID: 15380073
  23. N-terminal alpha-methylation of RCC1 is necessary for stable chromatin association and normal mitosis.
    Nat Cell Biol. 2007 May;9(5):596-603 PMID: 17435751
  24. Therapeutic potential of phosphoinositide 3-kinase inhibitors.
    Chem Biol. 2003 Mar;10(3):207-13 PMID: 12670534
  25. Epithelial cell polarity and cell junctions in Drosophila.
    Annu Rev Genet. 2001;35:747-84 PMID: 11700298
  26. Aggregation of microtubule initiation sites preceding neurite outgrowth in mouse neuroblastoma cells.
    Cell. 1979 Feb;16(2):253-63 PMID: 455435
  27. Centrosome aberrations: cause or consequence of cancer progression?
    Nat Rev Cancer. 2002 Nov;2(11):815-25 PMID: 12415252
  28. Polarity controls forces governing asymmetric spindle positioning in the Caenorhabditis elegans embryo.
    Nature. 2001 Feb 1;409(6820):630-3 PMID: 11214323
  29. Phosphatidylinositol 3-kinase, Cdc42, and Rac1 act downstream of Ras in integrin-dependent neurite outgrowth in N1E-115 neuroblastoma cells.
    Mol Cell Biol. 2000 Jan;20(1):158-72 PMID: 10594018
  30. Tetraploidy, aneuploidy and cancer.
    Curr Opin Genet Dev. 2007 Apr;17(2):157-62 PMID: 17324569
  31. Targeted cancer therapies based on the inhibition of DNA strand break repair.
    Oncogene. 2007 Dec 10;26(56):7816-24 PMID: 18066095
  32. Mechanisms for focusing mitotic spindle poles by minus end-directed motor proteins.
    J Cell Biol. 2005 Oct 24;171(2):229-40 PMID: 16247025
  33. Comparative study and improvement of current cell micro-patterning techniques.
    Lab Chip. 2007 Jun;7(6):672-80 PMID: 17538708
  34. Quantitative morphological signatures define local signaling networks regulating cell morphology.
    Science. 2007 Jun 22;316(5832):1753-6 PMID: 17588932
  35. Spindle multipolarity is prevented by centrosomal clustering.
    Science. 2005 Jan 7;307(5706):127-9 PMID: 15637283
  36. The drosophila protein asp is involved in microtubule organization during spindle formation and cytokinesis.
    J Cell Biol. 2001 May 14;153(4):637-48 PMID: 11352927
  37. Spatiotemporal feedback between actomyosin and focal-adhesion systems optimizes rapid cell migration.
    Cell. 2006 Jun 30;125(7):1361-74 PMID: 16814721
  38. Extra centrosomes and/or chromosomes prolong mitosis in human cells.
    Nat Cell Biol. 2008 Jun;10(6):748-51 PMID: 18469805
  39. In situ analysis of normal and abnormal patterns of the mitotic apparatus in cultured rat-kangaroo cells.
    Chromosoma. 1970;29(1):88-117 PMID: 4190066
  40. Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer.
    Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6427-31 PMID: 1650467
  41. Experimental and theoretical study of mitotic spindle orientation.
    Nature. 2007 May 24;447(7143):493-6 PMID: 17495931
  42. Identification of microtubule binding sites in the Ncd tail domain.
    Biochemistry. 1999 Feb 9;38(6):1838-49 PMID: 10026264
  43. The checkpoint control for anaphase onset does not monitor excess numbers of spindle poles or bipolar spindle symmetry.
    J Cell Sci. 1997 Feb;110 ( Pt 4):421-9 PMID: 9067594
  44. A novel member of the Ig superfamily, turtle, is a CNS-specific protein required for coordinated motor control.
    J Neurosci. 2001 May 1;21(9):3113-25 PMID: 11312296
  45. PAR proteins and the cytoskeleton: a marriage of equals.
    Curr Opin Cell Biol. 2006 Feb;18(1):86-94 PMID: 16364625
  46. Genes required for mitotic spindle assembly in Drosophila S2 cells.
    Science. 2007 Apr 20;316(5823):417-21 PMID: 17412918
  47. Amplified centrosomes in breast cancer: a potential indicator of tumor aggressiveness.
    Breast Cancer Res Treat. 2002 Sep;75(1):25-34 PMID: 12500932
  48. Genome-wide genetic analysis of polyploidy in yeast.
    Nature. 2006 Oct 5;443(7111):541-7 PMID: 17024086
  49. Centrosome amplification can initiate tumorigenesis in flies.
    Cell. 2008 Jun 13;133(6):1032-42 PMID: 18555779
  50. The good, the bad and the ugly: the practical consequences of centrosome amplification.
    Curr Opin Cell Biol. 2004 Feb;16(1):49-54 PMID: 15037304
  51. Integrin-mediated adhesion orients the spindle parallel to the substratum in an EB1- and myosin X-dependent manner.
    EMBO J. 2007 Mar 21;26(6):1487-98 PMID: 17318179
  52. DR-nm23 expression affects neuroblastoma cell differentiation, integrin expression, and adhesion characteristics.
    Med Pediatr Oncol. 2001 Jan;36(1):93-6 PMID: 11464913
  53. Spindle pole organization in Drosophila S2 cells by dynein, abnormal spindle protein (Asp), and KLP10A.
    Mol Biol Cell. 2005 Jul;16(7):3176-86 PMID: 15888542
  54. Echinoid is a component of adherens junctions that cooperates with DE-Cadherin to mediate cell adhesion.
    Dev Cell. 2005 Apr;8(4):493-504 PMID: 15809032
  55. Myosin-X: a molecular motor at the cell's fingertips.
    Trends Cell Biol. 2005 Oct;15(10):533-9 PMID: 16140532
  56. Endostatin regulates endothelial cell adhesion and cytoskeletal organization.
    Cancer Res. 2002 Apr 1;62(7):1944-7 PMID: 11929807
  57. Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen.
    Cancer Res. 2007 Jul 1;67(13):6342-50 PMID: 17616693
  58. Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability.
    Leukemia. 2005 Jul;19(7):1192-7 PMID: 15858613
  59. Parallel chemical genetic and genome-wide RNAi screens identify cytokinesis inhibitors and targets.
    PLoS Biol. 2004 Dec;2(12):e379 PMID: 15547975
  60. The kinesin-related protein, HSET, opposes the activity of Eg5 and cross-links microtubules in the mammalian mitotic spindle.
    J Cell Biol. 1999 Oct 18;147(2):351-66 PMID: 10525540
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1700908
Published
2008-08-15
Epub
2008-00-28
Pages
2189-203
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2518815
Subset
IM
Grants
NIGMS NIH HHS · R01 GM083299 · United States
NIGMS NIH HHS · GM 083299 · United States
Corrections
CommentIn
PMID: 18765784
External Links
PubMed source DOI: 10.1101/gad.1700908 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2