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Class III ß-Tubulin Mediates Sensitivity to Chemotherapeutic Drugs in Non–Small Cell Lung Cancer

¹ Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales, Australia and ² University of New South Wales, Sydney, New South Wales, Australia

Requests for reprints: Maria Kavallaris, Children's Cancer Institute Australia for Medical Research, Randwick, 2031 New South Wales, Australia. Phone: 61-29382-1823; Fax: 61-29382-1850; E-mail: m.kavallaris{at}ccia.unsw.edu.au.

First line therapy for non–small cell lung carcinoma (NSCLC) commonly includes combination therapy with a tubulin-binding agent (TBA) and a DNA-damaging agent. TBAs suppress microtubule dynamics by binding to the ß-tubulin subunit of /ß-tubulin, inducing mitotic arrest and apoptosis. Up-regulation of class III ß-tubulin (ßIII-tubulin) has been implicated in clinical resistance in NSCLC, ovarian and breast tumors treated in combination with a TBA and DNA-damaging agent. To investigate the functional significance of ßIII-tubulin in resistance to both these classes of agents, small interfering RNA (siRNA) was used to silence the expression of this isotype in two NSCLC cell lines, NCI-H460 and Calu-6. Reverse transcription-PCR and immunoblotting showed that ßIII-siRNA potently inhibited the expression of ßIII-tubulin, without affecting the expression of other major ß-tubulin isotypes. Clonogenic assays showed that ßIII-siRNA cells were significantly more sensitive to TBAs, paclitaxel, vincristine, and vinorelbine, and for the first time, DNA-damaging agents, cisplatin, doxorubicin, and etoposide compared with controls. Cell cycle analysis of H460 ßIII-siRNA cells showed reduced accumulation at the G₂-M boundary and an increase in the sub-G₁ population in response to TBA treatment compared with control cells. Importantly, ßIII-siRNA cells displayed a significant dose-dependent increase in Annexin V staining when treated with either paclitaxel or cisplatin, compared with controls. These findings have revealed a novel role for ßIII-tubulin in mediating response to both TBA and DNA-damaging agent therapy and may have important implications for improving the targeting and treatment of drug-refractory NSCLC. [Cancer Res 2007;67(19):9356–63]

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