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Kinesins and Cancer pp 117–133Cite as

Kinesin-13 Microtubule Depolymerizing Proteins as Targets for Cancer Therapy

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Abstract

The success of drugs that target mitotic spindle microtubules to treat cancer has spurred an interest in identifying other spindle proteins as potential drug targets that may be similarly effective yet have fewer side effects. The known activities of kinesin-13 family members to promote spindle bipolarity and faithful chromosome segregation, along with their ability to influence microtubule behavior, suggest that these proteins would be particularly effective targets for drug development. This chapter reviews the activities of kinesin-13 proteins in the context of how they might be manipulated to affect spindle structure and advance cancer treatment by direct targeting, by enhancing the effectiveness of other current treatments, or by reversing resistance to other treatments.

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References

  1. Desai A, Verma S, Mitchison TJ, Walczak CE (1999) Kin I kinesins are microtubule-destabilizing enzymes. Cell 96:69–78

    Article  CAS  PubMed  Google Scholar 

  2. Lawrence CJ et al (2004) A standardized kinesin nomenclature. J Cell Biol 167:19–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Miki H, Okada Y, Hirokawa N (2005) Analysis of the kinesin superfamily: insights into structure and function. Trends Cell Biol 15:467–476

    Article  CAS  PubMed  Google Scholar 

  4. Manning AL et al (2007) The kinesin-13 proteins Kif2a, Kif2b, and Kif2c/MCAK have distinct roles during mitosis in human cells. Mol Biol Cell 18:2970–2979

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Ems-McClung SC, Walczak CE (2010) Kinesin-13 s in mitosis: key players in the spatial and temporal organization of spindle microtubules. Semin Cell Dev Biol 21:276–282

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Moores CA, Milligan RA (2006) Lucky 13-microtubule depolymerisation by kinesin-13 motors. J Cell Sci 119:3905–3913

    Article  CAS  PubMed  Google Scholar 

  7. Walczak CE, Gayek S, Ohi R (2013) Microtubule-depolymerizing kinesins. Annu Rev Cell Dev Biol 29:417–441

    Article  CAS  PubMed  Google Scholar 

  8. Ganem NJ, Compton DA (2004) The KinI kinesin Kif2a is required for bipolar spindle assembly through a functional relationship with MCAK. J Cell Biol 166:473–478

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Skube SB, Chaverri JM, Goodson HV (2010) Effect of GFP tags on the localization of EB1 and EB1 fragments in vivo. Cytoskeleton 67:1–12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Ganguly A, Bhattacharya R, Cabral F (2012) Control of MCAK degradation and removal from centromeres. Cytoskeleton 69:303–311

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Welburn JPI, Cheeseman IM (2012) The microtubule-binding protein Cep170 promotes the targeting of the kinesin-13 depolymerase Kif2b to the mitotic spindle. Mol Biol Cell 23:4786–4795

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Wordeman L, Wagenbach M, Maney T (1999) Mutations in the ATP-binding domain affect the subcellular distribution of mitotic centromere-associated kinesin (MCAK). Cell Biol Int 23:275–286

    Article  CAS  PubMed  Google Scholar 

  13. Ganguly A, Bhattacharya R, Cabral F (2008) Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement. Cell Cycle 7:3187–3193

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Maney T, Hunter AW, Wagenbach M, Wordeman L (1998) Mitotic centromere-associated kinesin is important for anaphase chromosome segregation. J Cell Biol 142:787–801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Uehara R et al (2013) Aurora B and Kif2A control microtubule length for assembly of a functional central spindle during anaphase. J Cell Biol 202:623–636

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Bakhoum SF, Thompson SL, Manning AL, Compton DA (2009) Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat Cell Biol 11:27–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Manning AL et al (2010) CLASP1, astrin and Kif2b form a molecular switch that regulates kinetochore-microtubule dynamics to promote mitotic progression and fidelity. EMBO J 29:3531–3543

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Shrestha RL, Draviam VM (2013) Lateral to end-on conversion of chromosome-microtubule attachment requires kinesins CENP-E and MCAK. Curr Biol 23:1514–1526

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Helenius J, Brouhard G, Kalaidzidis Y, Diez S, Howard J (2006) The depolymerizing kinesin MCAK uses lattice diffusion to rapidly target microtubule ends. Nature 441:115–119

    Article  CAS  PubMed  Google Scholar 

  20. Ogawa T, Nitta R, Okada Y, Hirokawa N (2004) A common mechanism for microtubule destabilizers-M type kinesins stabilize curling of the protofilament using the class-specific neck and loops. Cell 116:591–602

    Article  CAS  PubMed  Google Scholar 

  21. Shipley K et al (2004) Structure of a kinesin microtubule depolymerization machine. EMBO J 23:1422–1432

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Cimini D et al (2001) Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J Cell Biol 153:517–527

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Kline-Smith SL, Khodjakov A, Hergert P, Walczak CE (2004) Depletion of centromeric MCAK leads to chromosome congression and segregation defects due to improper kinetochore attachments. Mol Biol Cell 15:1146–1159

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Ganguly A, Yang H, Pedroza M, Bhattacharya R, Cabral F (2011) Mitotic centromere associated kinesin (MCAK) mediates paclitaxel resistance. J Biol Chem 286:36378–36384

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Kline-Smith SL, Walczak CE (2002) The microtubule destabilizing kinesin XKCM1 regulates microtubule dynamic instability in cells. Mol Biol Cell 13:2718–2731

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Wordeman L, Wagenbach M, von Dassow G (2007) MCAK facilitates chromosome movement by promoting kinetochore microtubule turnover. J Cell Biol 179:869–879

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Ganguly A, Yang H, Cabral F (2011) Overexpression of mitotic centromere-associated kinesin stimulates microtubule detachment and confers resistance to paclitaxel. Mol Cancer Ther 10:929–937

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Sanhaji M, Friel CT, Wordeman L, Louwen F, Yuan J (2011) Mitotic centromere-associated kinesin (MCAK): a potential cancer drug target. Oncotarget 2:935–947

    PubMed Central  PubMed  Google Scholar 

  29. Zhang X, Lan W, Ems-McClung SC, Stukenberg PT, Walczak CE (2007) Aurora B phosphorylates multiple sites on mitotic centromere-associated kinesin to spatially and temporally regulate its function. Mol Biol Cell 18:3264–3276

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Andrews PD et al (2004) Aurora B regulates MCAK at the mitotic centromere. Dev Cell 6:253–268

    Article  CAS  PubMed  Google Scholar 

  31. Lan W et al (2004) Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity. Curr Biol 14:273–286

    Article  CAS  PubMed  Google Scholar 

  32. Zhang X, Ems-McClung SC, Walczak C (2008) Aurora A phosphorylates MCAK to control ran-dependent spindle bipolarity. Mol Biol Cell 19:2752–2765

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Moore A, Wordeman L (2004) The mechanism, function and regulation of depolymerizing kinesins during mitosis. Trends Cell Biol 14:537–546

    Article  CAS  PubMed  Google Scholar 

  34. Gorbsky GJ (2004) Mitosis: MCAK under the aura of aurora B. Curr Biol 14:R346–R348

    Article  CAS  PubMed  Google Scholar 

  35. Wang C-Q et al (2010) Overexpression of Kif2a promotes the progression and metastasis of squamous cell carcinoma of the oral tongue. Oral Oncol 46:65–69

    Article  PubMed  Google Scholar 

  36. Li G, Luna C, Qiu J, Epstein DL, Gonzalez P (2010) Targeting of integrin beta1 and kinesin 2alpha by microRNA 183. J Biol Chem 285:5461–5471

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Perou CM et al (1999) Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A 96:9212–9217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Shimo A et al (2008) Involvement of kinesin family member 2C/mitotic centromere-associated kinesin overexpression in mammary carcinogenesis. Cancer Sci 99:62–70

    CAS  PubMed  Google Scholar 

  39. Nakamura Y et al (2007) Clinicopathological and biological significance of mitotic centromere-associated kinesin overexpression in human gastric cancer. Br J Cancer 97:543–549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Ishikawa K et al (2008) Mitotic centromere-associated kinesin is a novel marker for prognosis and lymph node metastasis in colorectal cancer. Br J Cancer 98:1824–1829

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Gnjatic S et al (2010) NY-CO-58/KIF2C is overexpressed in a variety of solid tumors and induces frequent T cell responses in patients with colorectal cancer. Int J Cancer 127:381–393

    CAS  PubMed  Google Scholar 

  42. Scanlan MJ et al (2002) Cancer-related serological recognition of human colon cancer: identification of potential diagnostic and immunotherapeutic targets. Cancer Res 62:4041–4047

    CAS  PubMed  Google Scholar 

  43. Kawamoto M et al (2011) Identification of HLA-A *0201/-A*2402-restricted CTL epitope-peptides derived from a novel cancer/testis antigen, MCAK, and induction of a specific antitumor immune response. Oncol Rep 25:469–476

    CAS  PubMed  Google Scholar 

  44. Sircar K et al (2012) Mitosis phase enrichment with identification of mitotic centromere-associated kinesin as a therapeutic target in castration-resistant prostate cancer. PLoS One 7:e31259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Bie L, Zhao G, Wang Y-P, Zhang B (2012) Kinesin family member 2C (KIF2C/MCAK) is a novel marker for prognosis in human gliomas. Clin Neurol Neurosurg 114:356–360

    Article  PubMed  Google Scholar 

  46. Kumar A, Rajendran V, Sethumadhavan R, Purohit R (2013) Evidence of colorectal cancer-associated mutation in MCAK: a computational report. Cell Biochem Biophys 67:837–851

    Article  CAS  PubMed  Google Scholar 

  47. Rizk RS et al (2009) MCAK and paclitaxel have differential effects on spindle microtubule organization and dynamics. Mol Biol Cell 20:1639–1651

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Cassimeris L, Pryer NK, Salmon ED (1988) Real-time observation of microtubule dynamic instability in living cells. J Cell Biol 107:2223–2231

    Article  CAS  PubMed  Google Scholar 

  49. Honore S et al (2004) Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells. Cancer Res 64:4957–4964

    Article  CAS  PubMed  Google Scholar 

  50. Panda D, DeLuca K, Williams D, Jordan MA, Wilson L (1998) Antiproliferative mechanism of action of cryptophycin-52: kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends. Proc Natl Acad Sci U S A 95:9313–9318

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Yvon AM, Wadsworth P, Jordan MA (1999) Taxol suppresses dynamics of individual microtubules in living human tumor cells. Mol Biol Cell 10:947–959

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Yang H, Ganguly A, Cabral F (2010) Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs. J Biol Chem 285:32242–32250

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Ganguly A, Yang H, Cabral F (2010) Paclitaxel dependent cell lines reveal a novel drug activity. Mol Cancer Ther 9:2914–2923

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Rusan NM, Wadsworth P (2005) Centrosome fragments and microtubules are transported asymmetrically away from division plane in anaphase. J Cell Biol 168:21–28

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Keating TJ, Peloquin JG, Rodionov VI, Momcilovic D, Borisy GG (1997) Microtubule release from the centrosome. Proc Natl Acad Sci U S A 94:5078–5083

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Burbank KS, Groen AC, Perlman ZE, Fisher DS, Mitchison TJ (2006) A new method reveals microtubule minus ends throughout the meiotic spindle. J Cell Biol 175:369–375

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Mastronarde DN, McDonald KL, Ding R, McIntosh JR (1993) Interpolar spindle microtubules in PTK cells. J Cell Biol 123:1475–1489

    Article  CAS  PubMed  Google Scholar 

  58. Tulu US, Rusan NM, Wadsworth P (2003) Peripheral, non-centrosome-associated microtubules contribute to spindle formation in centrosome-containing cells. Curr Biol 13:1894–1899

    Article  CAS  PubMed  Google Scholar 

  59. Yang G et al (2007) Architectural dynamics of the meiotic spindle revealed by single-fluorophore imaging. Nat Cell Biol 9:1233–1242

    Article  CAS  PubMed  Google Scholar 

  60. Goshima G, Mayer M, Zhang N, Stuurman N, Vale RD (2008) Augmin: a protein complex required for centrosome-independent microtubule generation within the spindle. J Cell Biol 181:421–429

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Tournebize R et al (2000) Control of microtubule dynamics by the antagonistic activities of XMAP215 and XKCM1 in Xenopus egg extracts. Nat Cell Biol 2:13–19

    Article  CAS  PubMed  Google Scholar 

  62. Walczak CE, Mitchison TJ, Desai A (1996) XKCM1: a Xenopus kinesin-related protein that regulates microtubule dynamics during mitotic spindle assembly. Cell 84:37–47

    Article  CAS  PubMed  Google Scholar 

  63. Wilbur JD, Heald R (2013) Mitotic spindle scaling during Xenopus development by kif2a and importin alpha. Elife 2:e00290

    Article  PubMed Central  PubMed  Google Scholar 

  64. Schimizzi GV, Currie JD, Rogers SL (2010) Expression levels of a kinesin-13 microtubule depolymerase modulates the effectiveness of anti-microtubule agents. PLoS One 5:e11381

    Article  PubMed Central  PubMed  Google Scholar 

  65. Aoki S, Ohta K, Yamazaki T, Sugawara F, Sakaguchi K (2005) Mammalian mitotic centromere-associated kinesin (MCAK): a new molecular target of sulfoquinovosylacylglycerols novel antitumor and immunosuppressive agents. FEBS J 272:2132–2140

    Article  CAS  PubMed  Google Scholar 

  66. Ohta K et al (2000) Studies on a novel DNA polymerase inhibitor group, synthetic sulfoquinovosylacylglycerols: inhibitory action on cell proliferation. Mutat Res 467:139–152

    Article  CAS  PubMed  Google Scholar 

  67. Good JA, Skoufias DA, Kozielski F (2011) Elucidating the functionality of kinesins: an overview of small molecule inhibitors. Semin Cell Dev Biol 22:935–945

    Article  CAS  PubMed  Google Scholar 

  68. Rickert KW et al (2008) Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP. Arch Biochem Biophys 469:220–231

    Article  CAS  PubMed  Google Scholar 

  69. Hari M, Yang H, Zeng C, Canizales M, Cabral F (2003) Expression of class III β-tubulin reduces microtubule assembly and confers resistance to paclitaxel. Cell Motil Cytoskeleton 56:45–56

    Article  CAS  PubMed  Google Scholar 

  70. Bhattacharya R, Yang H, Cabral F (2011) Class V β-tubulin alters dynamic instability and stimulates microtubule detachment from centrosomes. Mol Biol Cell 22:1025–1034

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Bhattacharya R, Cabral F (2004) A ubiquitous β-tubulin disrupts microtubule assembly and inhibits cell proliferation. Mol Biol Cell 15:3123–3131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Yang H, Ganguly A, Yin S, Cabral F (2011) Megakaryocyte lineage-specific class VI β-tubulin suppresses microtubule dynamics, fragments microtubules, and blocks cell division. Cytoskeleton (Hoboken) 68:175–187

    Article  Google Scholar 

  73. Pitts TM, Davis SL, Eckhardt SG, Bradshaw-Pierce EL (2014) Targeting nuclear kinases in cancer: development of cell cycle kinase inhibitors. Pharmacol Ther 142:258–269

    Article  CAS  PubMed  Google Scholar 

  74. Zaganjor E et al (2014) Ras regulates kinesin 13 family members to control cell migration pathways in transformed human bronchial epithelial cells. Oncogene 33:5457–5466

    Article  CAS  PubMed  Google Scholar 

  75. Mikhailov A, Gundersen GG (1998) Relationship between microtubule dynamics and lamellipodium formation revealed by direct imaging of microtubules in cells treated with nocodazole or Taxol. Cell Motil Cytoskeleton 41:325–340

    Article  CAS  PubMed  Google Scholar 

  76. Ganguly A, Yang H, Sharma R, Patel KD, Cabral F (2012) The role of microtubules and their dynamics in cell migration. J Biol Chem 287:43359–43369

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Ganguly A, Yang H, Zhang H, Cabral F, Patel KD (2013) Microtubule dynamics control tail retraction in migrating vascular endothelial cells. Mol Cancer Ther 12:2837–2846

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, AB, T2N4Z6, Canada

    Anutosh Ganguly

  2. Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, TX, 77030, USA

    Fernando Cabral

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  1. Anutosh Ganguly
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  2. Fernando Cabral
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Correspondence to Fernando Cabral .

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Editors and Affiliations

  1. Chair, Department of Pharmaceutical and Biological Chemistry School of Pharmacy, University College London, London, United Kingdom

    Frank Kozielski, FSB

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Ganguly, A., Cabral, F. (2015). Kinesin-13 Microtubule Depolymerizing Proteins as Targets for Cancer Therapy. In: Kozielski, FSB, F. (eds) Kinesins and Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9732-0_8

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