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Microtubules and resistance to tubulin-binding agents

Nature Reviews Cancer volume 10, pages 194–204 (2010)Cite this article

Subjects

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.

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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.

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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.

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  1. Children's Cancer Institute Australia for Medical Research, Randwick, 2031, NSW, Australia

    Maria Kavallaris

  2. University of New South Wales, 2052, NSW, Australia

    Maria Kavallaris

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DATABASES

National Cancer Institute Drug Dictionary 

carboplatin

cisplatin

colchicine

docetaxel

epothilone B

paclitaxel

vinblastine

vincristine

vinorelbine

MiRBase 

miR-200c

FURTHER INFORMATION

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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.

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

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