Class III β-tubulin

Class III β-tubulin, otherwise known as βIII-tubulin (β3-tubulin) or β-tubulin III, is a microtubule element of the tubulin family found almost exclusively in neurons.

It is possible to use monoclonal antibodies and immunohistochemistry to identify neurons in samples of brain tissue, separating neurons from glial cells, which do not express Class III β-tubulin.

Role in Cancer

It has been reported that β3-tubulin is expressed in a wide variety of tumors. Overexpression of this isotype in clinical samples correlates with tumor aggressiveness, resistance to chemotherapeutic drugs, and poor patient survival.[1][2]

Mechanism

The β3 isotype increases tumor aggressiveness by two distinct mechanisms. Incorporation of this isotype makes microtubule networks hypostable, allowing them to resist the cytotoxic effects of microtubule stabilizing drugs like taxanes or epothilones. Mechanistically, it was found that overexpression of β3-tubulin increases the rate of microtubule detachment from microtubule organizing centers, an activity that is suppressed by drugs such as paclitaxel.[3]

Expression of β3-tubulin also makes cells more aggressive by altering their response to drug-induced suppression of microtubule dynamics.[4] Dynamic microtubules are needed for the cell migration that underlies processes such as tumor metastasis and angiogenesis. The dynamics are normally suppressed by low, subtoxic concentrations of microtubule drugs that also inhibit cell migration. However, incorporating β3-tubulin into microtubules increases the concentration of drug that is needed to suppress dynamics and inhibit cell migration. Thus, tumors that express β3-tubulin are not only resistant to the cytotoxic effects of microtubule targeted drugs, but also to their ability to suppress tumor metastasis. Moreover, expression of β3-tubulin also counteracts the ability of these drugs to inhibit angiogenesis which is normally another important facet of their action.

References

  1. ↑ Karki, R; Marini, M; Andreoli, M; He, S; Scambia, G; Shahabi, S; Ferlini, C (2013). "βIII-Tubulin: biomarker of taxane resistance or drug target?". Expert Opin Ther Targets. 17 (4): 461–72. doi:10.1517/14728222.2013.766170. PMID 23379899.
  2. ↑ Ferrandina, G; Zannoni, GF; Martinelli, E; Paglia, A; Gallotta, V; Mozzetti, S; Scambia, G; Ferlini, C (2006). "Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients.". Clin Cancer Res. 12 (9): 2774–9. doi:10.1158/1078-0432.CCR-05-2715. PMID 16675570.
  3. ↑ Ganguly, A; Cabral, F (2011). "New insights into mechanisms of resistance to microtubule inhibitors". Biochim Biophys Acta. 1816 (2): 2774–9. doi:10.1016/j.bbcan.2011.06.001. PMC 3202616Freely accessible. PMID 21741453.
  4. ↑ Ganguly, A; Yang, H; Cabral, F (2011). "Class III β-tubulin counteracts the ability of paclitaxel to inhibit cell migration.". Oncotarget. 2 (5): 368–377. PMC 3248193Freely accessible. PMID 21576762.
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