|Institution:||University of New South Wales|
|Department:||Women's & Children's Health|
|Full text PDF:||http://handle.unsw.edu.au/1959.4/53648|
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumour with a very poor prognosis. Treatment usually involves surgical resection, radiotherapy and the chemotherapeutic agent temozolomide (TMZ). GBM’s highly resistant nature frequently renders treatment ineffective. Understanding the mechanisms underlying the resistance phenotype could lead to improved therapeutic approaches. βIII-tubulin is a neuronal specific microtubule protein that is aberrantly expressed in GBM. Glioma cells of origin do not express it. In contrast, in gliomas, its high histological expression correlates with increasing tumour grade, the functional significance of which is unknown. The aim was to investigate the role of βIII-tubulin in GBM tumourigenesis and response to chemo- and radio-therapy. Immuno-histochemical staining for βIII-tubulin in patient samples of low and high grades of astrocytoma, including grade IV GBM confirmed previously reported increasing levels of βIII-tubulin with increasing grades, signifying its potential role in the aggressiveness of GBM. siRNA-mediated βIII-tubulin knockdown significantly reduced the formation of patient-derived primary GBM neurospheres. The knockdown did not affect either organisation of a microtubule network or cell proliferation rates in GBM cell lines. Furthermore, GBM cells could be significantly sensitised to TMZ and epothilone B upon βIII-tubulin knockdown. The observed increase in cell death post TMZ treatment was associated with enhanced drug-induced senescence. A functional association between βIII-tubulin and p53 accumulation was found, specifically, an increase in transactivation of p53. Additionally, the relationship between βIII tubulin and GBM response to radiotherapy was investigated. Silencing of βIII-tubulin in GBM did not increase radio-sensitivity. On examination of other cancers, both non-small cell lung cancer (NSCLC) and pancreatic cancer were significantly radio-sensitised upon βIII-tubulin knockdown. This study also reports a novel phosphorylation on βIII-tubulin residue that is involved in the microtubule dynamic instability. Considering the highly chemo- and radio- resistant nature of GBM, NSCLC and pancreatic cancer, this new data suggests that βIII tubulin knockdown could be used as a strategy to chemo- and radio-sensitise cancers, improve response to therapy and ultimately patient survival.