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Expression of the SEPT9_i4 isoform confers resistance to microtubule-interacting drugs

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Abstract

Background

The evolutionarily conserved septin family of genes encode GTP binding proteins involved in a variety of cellular functions including cytokinesis, apoptosis, membrane dynamics and vesicle trafficking. Septin proteins can form hetero-oligomeric complexes and interact with other proteins including actin and tubulin. The human SEPT9 gene on chromosome 17q25.3 has a complex genomic architecture with 18 different transcripts that can encode 15 distinct polypeptides. Two distinct transcripts with unique 5′ ends (SEPT9_v4 and SEPT9_v4*) encode the same protein. In tumours the ratio of these transcripts changes with elevated levels of SEPT9_v4* mRNA, a transcript that is translated with enhanced efficiency leading to increased SEPT9_i4 protein.

Methods

We have examined the effect of over-expression of SEPT9_i4 on the dynamics of microtubule polymer mass in cultured cells.

Results

We show that the microtubule network in SEPT9_i4 over-expressing cells resists disruption by paclitaxel or cold incubation but also repolymerises tubulin more slowly after microtubule depolymerisation. Finally we show that SEPT9_i4 over-expressing cells have enhanced survival in the presence of clinically relevant microtubule acting drugs but not after treatment with DNAinteracting agents.

Conclusions

Given that SEPT9 over-expression is seen in diverse tumours and in particular ovarian and breast cancer, such data indicate that SEPT9_v4 expression may be clinically relevant and contribute to some forms of drug resistance.

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Acknowledgements

We are grateful for the financial support of QUB Faculty of Medicine, WellBeing of Women, Action Cancer, The Pathological Society of Great Britain and Ireland, The Hilary Curry Fund and NI HPSS R and D Office.

Conflict of interest

Richard Kennedy is also an employee of Almac Diagnostics, 19 Seagoe Industrial Estate, Craigavon, UK BT63 5QD.

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Authors and Affiliations

  1. Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, BT9 7AB, UK

    Alex D. Chacko, Simon S. McDade, Severine Chanduloy, Stewart W. Church, Richard Kennedy & S. E. Hilary Russell

  2. Department of Gynaecology, Tower Block, Belfast City Hospital, Belfast, BT9 7AB, UK

    John Price

  3. Departments of Molecular Oncology and Pathology & Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh, 11211, Saudi Arabia

    Peter A. Hall

  4. College of Medicine, Alfaisal University, PO Box 50927, Riyadh, 11533, Saudi Arabia

    Peter A. Hall

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  1. Alex D. Chacko
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  2. Simon S. McDade
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Corresponding author

Correspondence to S. E. Hilary Russell.

Additional information

Alex D Chacko and Simon S McDade have contributed equally to this work

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Chacko, A.D., McDade, S.S., Chanduloy, S. et al. Expression of the SEPT9_i4 isoform confers resistance to microtubule-interacting drugs. Cell Oncol. 35, 85–93 (2012). https://doi.org/10.1007/s13402-011-0066-0

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