Microtubules and resistance to tubulin-binding agents

A Corrigendum to this article was published on 05 March 2010

This article has been updated

Key Points

  • Microtubules are required for many aspects of cellular function, including mitosis. This has made them an attractive target for the development of cancer drugs.

  • Although drugs that target tubulin and microtubules are widely used in the clinic, resistance — both inherent and acquired — is common.

  • Understanding the function of tubulin in cancer development and resistance to tubulin-binding agents (TBAs) might aid the development of more effective drugs.

  • The expression of different β-tubulin isotypes is disrupted in cancer cells, and understanding how this contributes to disease progression and drug resistance is essential. Overexpression or aberrant expression of βIII-tubulin can affect the response of tumour cells to TBAs. The mechanisms that underlie this are currently unclear. Understanding the role of the other β-tubulin isotypes in cancer development is also at an early stage.

  • Proteins that regulate microtubules, such as microtubule-associated proteins and stathmin, are also implicated in drug resistance. How, mechanistically, these proteins influence resistance to TBAs is under investigation.

  • Changes to the actin cytoskeleton also contribute to drug resistance but how such changes relate to the microtubule system needs further clarification.

Abstract

Microtubules are dynamic structures composed of α–β-tubulin heterodimers that are essential in cell division and are important targets for cancer drugs. Mutations in β-tubulin that affect microtubule polymer mass and/or drug binding are associated with resistance to tubulin-binding agents such as paclitaxel. The aberrant expression of specific β-tubulin isotypes, in particular βIII-tubulin, or of microtubule-regulating proteins is important clinically in tumour aggressiveness and resistance to chemotherapy. In addition, changes in actin regulation can also mediate resistance to tubulin-binding agents. Understanding the molecular mechanisms that mediate resistance to tubulin-binding agents will be vital to improve the efficacy of these agents.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Microtubule changes during the cell cycle.
Figure 2: Mechanisms of tubulin-binding agent resistance.
Figure 3: Effects of endogenous proteins and tubulin-binding agents on microtubule stability.

Change history

  • 04 March 2010

    On page 202 of this article, extracellular matrix transforming growth factor–β1 (TGFβ1), should have read extracellular matrix transforming growth factor–β induced (TGFβI). This has been corrected.

References

  1. 1

    Verhey, K. J. & Gaertig, J. The tubulin code. Cell Cycle 6, 2152–2160 (2007).

    CAS  Article  Google Scholar 

  2. 2

    Pepperkok, R., Bre, M. H., Davoust, J. & Kreis, T. E. Microtubules are stabilized in confluent epithelial cells but not in fibroblasts. J. Cell Biol. 111, 3003–3012 (1990).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Saxton, W. M. et al. Tubulin dynamics in cultured mammalian cells. J. Cell Biol. 99, 2175–2186 (1984).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Rusan, N. M., Fagerstrom, C. J., Yvon, A. M. & Wadsworth, P. Cell cycle-dependent changes in microtubule dynamics in living cells expressing green fluorescent protein-α tubulin. Mol. Biol. Cell 12, 971–980 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Zhai, Y., Kronebusch, P. J., Simon, P. M. & Borisy, G. G. Microtubule dynamics at the G2/M transition: abrupt breakdown of cytoplasmic microtubules at nuclear envelope breakdown and implications for spindle morphogenesis. J. Cell Biol. 135, 201–214 (1996).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer 4, 253–265 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Kavallaris, M., Don, S. & Verrills, N. M. in Microtubule Targets in Cancer Therapy (ed. Fojo, A.) 84–106 (Humana, Totowa, New Jersey, 2008).

    Google Scholar 

  8. 8

    Perez, E. A. Microtubule inhibitors: differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol. Cancer Ther. 8, 2086–2095 (2009).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Downing, K. H. Structural basis for the interaction of tubulin with proteins and drugs that affect microtubule dynamics. Annu. Rev. Cell Dev. Biol. 16, 89–111 (2000).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Nettles, J. H. et al. The binding mode of epothilone A on α, β-tubulin by electron crystallography. Science 305, 866–869 (2004). The first high-resolution crystal structure that described binding sites for epothilone A on α–β-tubulin.

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Rieder, C. L. & Maiato, H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev. Cell 7, 637–651 (2004).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Gascoigne, K. E. & Taylor, S. S. How do anti-mitotic drugs kill cancer cells? J. Cell Sci. 122, 2579–2585 (2009).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Gascoigne, K. E. & Taylor, S. S. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14, 111–122 (2008). The first comprehensive study showing that there is cell-to-cell variation and intra-cell variation in response to anti-mitotic drugs.

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Shi, J., Orth, J. D. & Mitchison, T. Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5. Cancer Res. 68, 3269–3276 (2008).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Steen, J. A. et al. Different phosphorylation states of the anaphase promoting complex in response to antimitotic drugs: a quantitative proteomic analysis. Proc. Natl Acad. Sci. USA 105, 6069–6074 (2008).

    CAS  Article  Google Scholar 

  16. 16

    Brito, D. A., Yang, Z. & Rieder, C. L. Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied. J. Cell Biol. 182, 623–629 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Brito, D. A. & Rieder, C. L. The ability to survive mitosis in the presence of microtubule poisons differs significantly between human nontransformed (RPE-1) and cancer (U2OS, HeLa) cells. Cell Motil. Cytoskeleton 66, 437–447 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Brito, D. A. & Rieder, C. L. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr. Biol. 16, 1194–1200 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Vakoc, B. J. et al. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nature Med. 15, 1219–1223 (2009).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Luduena, R. F. Multiple forms of tubulin: different gene products and covalent modifications. Int. Rev. Cytol. 178, 207–275 (1998).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Verdier-Pinard, P. et al. Tubulin proteomics: towards breaking the code. Anal. Biochem. 384, 197–206 (2009). A detailed review of how proteomics is being used to identify tubulin isotypes and post-translational modifications of isotypes.

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Hammond, J. W., Cai, D. & Verhey, K. J. Tubulin modifications and their cellular functions. Curr. Opin. Cell Biol. 20, 71–76 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Freedman, H., Huzil, J. T., Luchko, T., Luduena, R. F. & Tuszynski, J. A. Identification and characterization of an intermediate taxol binding site within microtubule nanopores and a mechanism for tubulin isotype binding selectivity. J. Chem. Inf. Model 49, 424–436 (2009).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Westermann, S. & Weber, K. Post-translational modifications regulate microtubule function. Nature Rev. Mol. Cell Biol. 4, 938–947 (2003).

    CAS  Article  Google Scholar 

  25. 25

    O'Brate, A. & Giannakakou, P. The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist. Updat. 6, 313–322 (2003).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Bhalla, K. N. Microtubule-targeted anticancer agents and apoptosis. Oncogene 22, 9075–9086 (2003).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Mollinedo, F. & Gajate, C. Microtubules, microtubule-interfering agents and apoptosis. Apoptosis 8, 413–450 (2003).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Esteve, M. A., Carre, M. & Braguer, D. Microtubules in apoptosis induction: are they necessary? Curr. Cancer Drug Targets 7, 713–729 (2007).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Li, R., Moudgil, T., Ross, H. J. & Hu, H. M. Apoptosis of non-small-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim. Cell Death Differ. 12, 292–303 (2005).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Ferrandina, G. et al. Class III β-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients. Clin. Cancer Res. 12, 2774–2779 (2006).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Kavallaris, M. et al. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific β-tubulin isotypes. J. Clin. Invest. 100, 1282–1293 (1997). The first report describing alterations in β-tubulin isotype expression in taxol-resistant clinical samples.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Martello, L. A. et al. Elevated levels of microtubule destabilizing factors in a taxol-resistant/dependent A549 cell line with an α-tubulin mutation. Cancer Res. 63, 1207–1213 (2003).

    CAS  PubMed  Google Scholar 

  33. 33

    Don, S. et al. Neuronal-associated microtubule proteins class III β-tubulin and MAP2c in neuroblastoma: role in resistance to microtubule-targeted drugs. Mol. Cancer Ther. 3, 1137–1146 (2004).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Rouzier, R. et al. Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc. Natl Acad. Sci. USA 102, 8315–8320 (2005).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Tommasi, S. et al. Cytoskeleton and paclitaxel sensitivity in breast cancer: the role of β-tubulins. Int. J. Cancer 120, 2078–2085 (2007).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Seve, P. & Dumontet, C. Is class III β-tubulin a predictive factor in patients receiving tubulin-binding agents? Lancet Oncol. 9, 168–175 (2008).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Pasquier, E. & Kavallaris, M. Microtubules: a dynamic target in cancer therapy. IUBMB Life 60, 165–170 (2008).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Berrieman, H. K., Lind, M. J. & Cawkwell, L. Do β-tubulin mutations have a role in resistance to chemotherapy? Lancet Oncol. 5, 158–164 (2004).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Hodgkinson, J. E., Clark, H. J., Kaplan, R. M., Lake, S. L. & Matthews, J. B. The role of polymorphisms at β tubulin isotype 1 codons 167 and 200 in benzimidazole resistance in cyathostomins. Int. J. Parasitol. 38, 1149–1160 (2008).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Sale, S. et al. Conservation of the class I β-tubulin gene in human populations and lack of mutations in lung cancers and paclitaxel-resistant ovarian cancers. Mol. Cancer Ther. 1, 215–225 (2002).

    CAS  PubMed  Google Scholar 

  41. 41

    Katsetos, C. D., Herman, M. M. & Mork, S. J. Class III β-tubulin in human development and cancer. Cell. Motil. Cytoskeleton 55, 77–96 (2003).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Katsetos, C. D., Draberova, E., Legido, A., Dumontet, C. & Draber, P. Tubulin targets in the pathobiology and therapy of glioblastoma multiforme. I. class III β-tubulin. J. Cell Physiol. 221, 505–513 (2009). A detailed review of βIII-tubulin expression in glioblastoma.

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Lee, K. M. et al. Class III β-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia. Histopathology 51, 539–546 (2007).

    CAS  PubMed  Article  Google Scholar 

  44. 44

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

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Kamath, K., Wilson, L., Cabral, F. & Jordan, M. A. βIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability. J. Biol. Chem. 280, 12902–12907 (2005).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Kavallaris, M., Burkhart, C. A. & Horwitz, S. B. Antisense oligonucleotides to class III β-tubulin sensitize drug-resistant cells to taxol. Br. J. Cancer 80, 1020–1025 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Liu, B., Staren, E., Iwamura, T., Appert, H. & Howard, J. Taxotere resistance in SUIT: taxotere resistance in pancreatic carcinoma cell line SUIT 2 and its sublines. World J. Gastroenterol. 7, 855–859 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Gan, P. P., Pasquier, E. & Kavallaris, M. Class III β-tubulin mediates sensitivity to chemotherapeutic drugs in non small cell lung cancer. Cancer Res. 67, 9356–9363 (2007).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Raspaglio, G. et al. Hypoxia induces class III β-tubulin gene expression by HIF-1α binding to its 3′ flanking region. Gene 409, 100–108 (2008). The demonstration that hypoxia can induce βIII-tubulin expression in some cell types.

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Cicchillitti, L. et al. Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin. Mol. Cancer Ther. 7, 2070–2079 (2008).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Dennis, K., Uittenbogaard, M., Chiaramello, A. & Moody, S. A. Cloning and characterisation of the 5′-flanking region of the rat neuron-specific class III β-tubulin gene. Gene 294, 269–277 (2002).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Seve, P. et al. Expression of class III β-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy. Clin. Cancer Res. 11, 5481–5486 (2005). This paper provided strong evidence for a role for βIII-tubulin in clinical outcome in NSCLC.

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Seve, P. et al. Class III β-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol. Cancer Ther. 4, 2001–2007 (2005).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Portyanko, A., Kovalev, P., Gorgun, J. & Cherstvoy, E. βIII-tubulin at the invasive margin of colorectal cancer: possible link to invasion. Virchows Arch. 454, 541–548 (2009).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Cochrane, D. R., Spoelstra, N. S., Howe, E. N., Nordeen, S. K. & Richer, J. K. MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents. Mol. Cancer Ther. 8, 1055–1066 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Aoki, D. et al. Favourable prognosis with modified dosing of docetaxel and cisplatin in Japanese patients with ovarian cancer. Anticancer Res. 29, 561–566 (2009).

    CAS  PubMed  Google Scholar 

  57. 57

    Ferrandina, G. et al. Expression of class III β tubulin in cervical cancer patients administered preoperative radiochemotherapy: correlation with response to treatment and clinical outcome. Gynecol. Oncol. 104, 326–330 (2007).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Caracciolo, V. et al. Differential expression and cellular distribution of γ-tubulin and βIII-tubulin in medulloblastomas and human medulloblastoma cell lines. J. Cell Physiol. (in the press).

  59. 59

    Mhaidat, N. M., Thorne, R. F., de Bock, C. E., Zhang, X. D. & Hersey, P. Melanoma cell sensitivity to docetaxel-induced apoptosis is determined by class III β-tubulin levels. FEBS Lett. 582, 267–272 (2008).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Akasaka, K. et al. Loss of class III β-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells. J. Invest. Dermatol. 129, 1516–1526 (2009).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Bernard-Marty, C. et al. Microtubule-associated parameters as predictive markers of docetaxel activity in advanced breast cancer patients: results of a pilot study. Clin. Breast Cancer 3, 341–345 (2002).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Dozier, J. H. et al. β class II tubulin predominates in normal and tumor breast tissues. Breast Cancer Res. 5, R157–R169 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Cucchiarelli, V. et al. β-tubulin isotype classes II and V expression patterns in nonsmall cell lung carcinomas. Cell. Motil. Cytoskeleton 65, 675–685 (2008).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Blade, K., Menick, D. R. & Cabral, F. Overexpression of class I, II or IVb β-tubulin isotypes in CHO cells is insufficient to confer resistance to paclitaxel. J. Cell Sci. 112, 2213–2221 (1999). A detailed functional study demonstrating that exogenous expression of βI-, βII- or βIVb-tubulin does not influence sensitivity to paclitaxel.

    CAS  PubMed  Google Scholar 

  65. 65

    Burkhart, C. A., Kavallaris, M. & Band Horwitz, S. The role of β-tubulin isotypes in resistance to antimitotic drugs. Biochim. Biophys. Acta 1471, O1–O9 (2001).

    CAS  PubMed  Google Scholar 

  66. 66

    Gan, P. P. & Kavallaris, M. Tubulin-targeted drug action: functional significance of class II and class IVb β-tubulin in vinca alkaloid sensitivity. Cancer Res. 68, 9817–9824 (2008). The first functional evidence that βII- and βIVb-tubulin mediate sensitivity to vinca alkaloids.

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Mozzetti, S. et al. Molecular mechanisms of patupilone resistance. Cancer Res. 68, 10197–10204 (2008).

    CAS  PubMed  Article  Google Scholar 

  68. 68

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Thomas, E. et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J. Clin. Oncol. 25, 3399–3406 (2007).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Thomas, E. S. et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J. Clin. Oncol. 25, 5210–5217 (2007).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Ten Bokkel Huinink, W. W. et al. Safety and efficacy of patupilone in patients with advanced ovarian, primary fallopian, or primary peritoneal cancer: a Phase I, open-label, dose-escalation study. J. Clin. Oncol. 27, 3097–3103 (2009).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Sabbatini, P. & Spriggs, D. R. Epothilones: better or more of the same? J. Clin. Oncol. 27, 3079–3081 (2009).

    PubMed  Article  Google Scholar 

  73. 73

    Vansteenkiste, J. et al. Phase II clinical trial of the epothilone B analog, ixabepilone, in patients with non small-cell lung cancer whose tumors have failed first-line platinum-based chemotherapy. J. Clin. Oncol. 25, 3448–3455 (2007).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Dumontet, C., Jordan, M. A. & Lee, F. F. Ixabepilone: targeting βIII-tubulin expression in taxane-resistant malignancies. Mol. Cancer Ther. 8, 17–25 (2009).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Magnani, M. et al. The βI/βIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies. FEBS J. 273, 3301–3310 (2006).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Tanaka, S. et al. Tau expression and efficacy of paclitaxel treatment in metastatic breast cancer. Cancer Chemother. Pharmacol. 64, 341–346 (2009).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Ferlini, C. et al. Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work? Curr. Cancer Drug Targets. 7, 704–712 (2007).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Baselga, J. et al. Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer. J. Clin. Oncol. 27, 526–534 (2009).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Murphy, M., Hinman, A. & Levine, A. J. Wild-type p53 negatively regulates the expression of a microtubule-associated protein. Genes Dev. 10, 2971–2980 (1996).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Zhang, C. C. et al. DNA damage increases sensitivity to vinca alkaloids and decreases sensitivity to taxanes through p53-dependent repression of microtubule-associated protein 4. Cancer Res. 59, 3663–3670 (1999).

    CAS  PubMed  Google Scholar 

  81. 81

    Bash-Babula, J. et al. A Phase I/pilot study of sequential doxorubicin/vinorelbine: effects on p53 and microtubule-associated protein 4. Clin. Cancer Res. 8, 1057–1064 (2002).

    CAS  PubMed  Google Scholar 

  82. 82

    Gigant, B. et al. Structural basis for the regulation of tubulin by vinblastine. Nature 435, 519–522 (2005).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Rana, S., Maples, P. B., Senzer, N. & Nemunaitis, J. Stathmin 1: a novel therapeutic target for anticancer activity. Expert Rev. Anticancer Ther. 8, 1461–1470 (2008).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    McGrogan, B. T., Gilmartin, B., Carney, D. N. & McCann, A. Taxanes, microtubules and chemoresistant breast cancer. Biochim. Biophys. Acta 1785, 96–132 (2008).

    CAS  PubMed  Google Scholar 

  85. 85

    Belletti, B. et al. Stathmin activity influences sarcoma cell shape, motility, and metastatic potential. Mol. Biol. Cell 19, 2003–2013 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86

    Alli, E., Yang, J. M., Ford, J. M. & Hait, W. N. Reversal of stathmin-mediated resistance to paclitaxel and vinblastine in human breast carcinoma cells. Mol. Pharmacol. 71, 1233–1240 (2007).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Su, D. et al. Stathmin and tubulin expression and survival of ovarian cancer patients receiving platinum treatment with and without paclitaxel. Cancer 115, 2453–2463 (2009).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Devred, F. et al. Stathmin/Op18 is a novel mediator of vinblastine activity. FEBS Lett. 582, 2484–2488 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Verrills, N. M., Walsh, B. J., Cobon, G. S., Hains, P. G. & Kavallaris, M. Proteome analysis of vinca alkaloid response and resistance in acute lymphoblastic leukemia reveals novel cytoskeletal alterations. J. Biol. Chem. 278, 45082–45093 (2003).

    CAS  PubMed  Article  Google Scholar 

  90. 90

    Rodriguez, O. C. et al. Conserved microtubule–actin interactions in cell movement and morphogenesis. Nature Cell Biol. 5, 599–609 (2003).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Hall, A. The cytoskeleton and cancer. Cancer Metastasis Rev. 28, 5–14 (2009).

    PubMed  Article  Google Scholar 

  92. 92

    Verrills, N. M. & Kavallaris, M. Drug resistance mechanisms in cancer cells: a proteomics perspective. Curr. Opin. Mol. Ther. 5, 258–265 (2003).

    CAS  PubMed  Google Scholar 

  93. 93

    Verrills, N. M. et al. Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia — an in vivo study. Proteomics 6, 1681–1694 (2006).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Verrills, N. M. et al. Alterations in γ-actin and tubulin-targeted drug resistance in childhood leukemia. J. Natl Cancer Inst. 98, 1363–1374 (2006). The finding that a component of the actin cytoskeleton, γ-actin, can mediate sensitivity to TBAs.

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Dan, S. et al. An integrated database of chemosensitivity to 55 anticancer drugs and gene expression profiles of 39 human cancer cell lines. Cancer Res. 62, 1139–1147 (2002).

    CAS  PubMed  Google Scholar 

  96. 96

    Bernard, O. Lim kinases, regulators of actin dynamics. Int. J. Biochem. Cell Biol. 39, 1071–1076 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Acevedo, K., Moussi, N., Li, R., Soo, P. & Bernard, O. LIM kinase 2 is widely expressed in all tissues. J. Histochem. Cytochem. 54, 487–501 (2006).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Sumi, T., Hashigasako, A., Matsumoto, K. & Nakamura, T. Different activity regulation and subcellular localization of LIMK1 and LIMK2 during cell cycle transition. Exp. Cell Res. 312, 1021–1030 (2006).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Po'uha, S. T., Shum, M. S., Goebel, A., Bernard, O. & Kavallaris, M. LIM-kinase 2, a regulator of actin dynamics, is involved in mitotic spindle integrity and sensitivity to microtubule-destabilizing drugs. Oncogene 29, 597–607 (2010).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Ahmed, A. A. et al. The extracellular matrix protein TGFBI induces microtubule stabilization and sensitizes ovarian cancers to paclitaxel. Cancer Cell 12, 514–527 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101

    Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Rev. Cancer 9, 665–674 (2009).

    CAS  Article  Google Scholar 

  102. 102

    Teicher, B. A. Acute and chronic in vivo therapeutic resistance. Biochem. Pharmacol. 77, 1665–1673 (2009).

    CAS  PubMed  Article  Google Scholar 

  103. 103

    Cabral, F. Factors determining cellular mechanisms of resistance to antimitotic drugs. Drug Resist. Updat. 4, 3–8 (2001).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Schiff, P. B., Horwitz, S. B. Taxol stabilizes microtubules in mouse fibroblast cells. Proc. Natl Acad. Sci. USA 77, 1561–1565 (1980).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Hunt, J. T. Discovery of ixabepilone. Mol. Cancer Ther. 8, 275–281 (2009).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Howard, J. & Hyman, A. A. Dynamics and mechanics of the microtubule plus end. Nature 422, 753–758 (2003).

    CAS  Article  PubMed  Google Scholar 

  107. 107

    Heald, R. & Nogales, E. Microtubule dynamics. J. Cell Sci. 115, 3–4 (2002).

    CAS  PubMed  Google Scholar 

  108. 108

    Rubin, C. I. & Atweh, G. F. The role of stathmin in the regulation of the cell cycle. J. Cell Biochem. 93, 242–250 (2004).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Verrills, N. M. & Kavallaris, M. Improving the targeting of tubulin-binding agents: lessons from drug resistance studies. Curr. Pharm. Des. 11, 1719–1733 (2005).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Mozzetti, S. et al. Class III β-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin. Cancer Res. 11, 298–305 (2005).

    CAS  PubMed  Google Scholar 

  111. 111

    Ohishi, Y. et al. Expression of β-tubulin isotypes in human primary ovarian carcinoma. Gynecol. Oncol. 105, 586–592 (2007).

    CAS  PubMed  Article  Google Scholar 

  112. 112

    Hasegawa, S. et al. Prediction of response to docetaxel by quantitative analysis of class I and III β-tubulin isotype mRNA expression in human breast cancers. Clin. Cancer Res. 9, 2992–2997 (2003).

    CAS  PubMed  Google Scholar 

  113. 113

    Paradiso, A. et al. Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. Ann. Oncol. 16, iv14–iv19 (2005).

    PubMed  Article  Google Scholar 

  114. 114

    Rosell, R. et al. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Oncogene 22, 3548–3553 (2003).

    CAS  PubMed  Article  Google Scholar 

  115. 115

    Koh, Y. et al. Class III β-tubulin, but not ERCC1, is a strong predictive and prognostic marker in locally advanced head and neck squamous cell carcinoma. Ann. Oncol. 20, 1414–1419 (2009).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Urano, N. et al. Clinical significance of class III β-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer. Int. J. Oncol. 28, 375–381 (2006).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author was supported by a Senior Research Fellowship, grants from the National Health and Medical Research Council and a grant from the Cancer Council New South Wales. I thank E. Pasquier and J. Mccarroll for their critical reading of and suggestions for the review.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary 

carboplatin

cisplatin

colchicine

docetaxel

epothilone B

paclitaxel

vinblastine

vincristine

vinorelbine

MiRBase 

miR-200c

FURTHER INFORMATION

Maria Kavallaris' homepage

Glossary

Centrosome

This organelle is also called the 'microtubule-organizing centre' and is located near the nucleus in the cytoplasm.

Mitotic asters

Microtubules that radiate from the mitotic spindle poles to the cell cortex. Asters are involved in the positioning and alignment of the spindle poles during cell division.

Kinetochore

A complicated protein assembly that links the specialized areas of condensed chromosomes (centromeres) to the microtubule-based mitotic spindle.

Intravital microscopy

This technique uses a sophisticated research microscope that allows the microcirculation and complex biological interactions in organs to be directly visualized in real time in anaesthetized animals.

E-box

A consensus DNA site recognized by the transcription factor MYC.

Punctae

A speckled staining pattern in cells that is often made up of proteins or protein aggregates.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kavallaris, M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 10, 194–204 (2010). https://doi.org/10.1038/nrc2803

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing