|Cancer||Cell death||Cell cycle||Cytoskeleton||Exo/endocytosis||Differentiation||Division||Organelles||Signalling||Stem cells||Trafficking|
A mutation in β-tubulin and a sustained dependence on androgen receptor signalling in a newly established docetaxel-resistant prostate cancer cell line
Takahito Hara*1, Kazutaka Ushio*, Mayumi Nishiwaki*, Jin Kouno*, Hideo Araki*, Yukiko Hikichi*, Masahiko Hattori*, Yumi Imai† and Masuo Yamaoka*
*Pharmacology Research Laboratories, Takeda Pharmaceutical Company Limited, Tsukuba, Japan, and †Discovery Research Center, Takeda Pharmaceutical Company Limited, Osaka, Japan
The mechanisms of docetaxel resistance in PC (prostate cancer) are unclear because of the lack of suitable experimental models, and no effective treatment exists for docetaxel-resistant PC. We established a docetaxel-resistant cell line, LNDCr, from an androgen-refractory PC cell line, LNCaP-hr, by intermittent exposure to docetaxel in vitro. The LNDCr cells harboured an F270I mutation in class I β-tubulin, and demonstrated impaired tubulin polymerization by docetaxel. AR signalling was sustained in LNDCr cells, and AR knockdown suppressed the growth of LNDCr cells. These results suggest that an acquired mutation in β-tubulin is associated with docetaxel resistance in PC and that a novel AR-targeted therapy is effective for docetaxel-resistant PC.
Key words: androgen receptor, docetaxel, drug resistance, prostate cancer, tubulin
Abbreviations: ABC, ATP-binding cassette, AR, androgen receptor, DCC-FBS, dextran charcoal-stripped fetal bovine serum, FBS, fetal bovine serum, PC, prostate cancer, PSA, prostate-specific antigen, siRNA, small interfering RNA
1To whom correspondence should be addressed (email Hara_Takahito@takeda.co.jp).
Received 15 May 2009/13 October 2009; accepted 22 October 2009
Published as Cell Biology International Immediate Publication 22 October 2009, doi:10.1042/CBI20090030
© 2010 The Author(s) Journal compilation. © 2010 Portland Press Ltd