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

• Published in: Cellular oncology (Dordrecht) Vol. 35; no. 2; pp. 85 - 93
• Main Authors: Chacko, Alex D., McDade, Simon S., Chanduloy, Severine, Church, Stewart W., Kennedy, Richard, Price, John, Hall, Peter A., Russell, S. E. Hilary
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.04.2012
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; DNA Damage; Drug Resistance, Neoplasm - drug effects; Flow Cytometry; Humans; Ice; Microtubules - drug effects; Microtubules - metabolism; Oncology; Original Paper; Paclitaxel - pharmacology; Pathology; Polymerization - drug effects; Protein Isoforms - metabolism; Septins - metabolism; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; Vinorelbine; SEPT9; Drug resistance; Septin; Microtubules
• ISSN: 2211-3428; 2211-3436
• DOI: 10.1007/s13402-011-0066-0

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.