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Sangrajrang S , Denoulet P , Laing NM , Tatoud R , Millot G , Calvo F , Tew KD , Fellous A
Association of estramustine resistance in human prostatic carcinoma cells with modified patterns of tubulin expression
Biochemical Pharmacology. 1998 Feb 1;55(3) :325-331
PMID: ISI:000071042100012   
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Estramustine (EM) is an antimicrotubule drug used in the treatment of hormone refractory advanced prostate cancer. To investigate the mechanism of resistance re, EM, we compared its effects on human prostate cancer cells (DU145) and an estramustine-resistant derived cell line (E4). Immunofluorescence demonstrated that EM caused depolymerization of microtubules and blocked cells in mitosis in DU145 cells, with less effect in E4 cells. Using tubulin isotype-specific antibodies, a threefold increase in beta III and similar to twofold increase in beta I + II isotype in E4 cells compared to DU145 cells were observed. A most interesting observation concerned an increase in the posttranslational modification of alpha-tubulin of both polyglutamylation and acetylation in the E4 cells. Significant to this observation, using direct EM photoaffinity labeling of tubulin, drug binding to the most acidic posttranslationally modified forms of alpha-tubulin was shown to be minimal. Taken together, these results indicate that the modification of the tubulin expression pattern may be responsible for estramustine resistance by both lowering the amount of drug bound to microtubules and inducing more stable microtubules. (C) 1998 Elsevier Science Inc.
Times Cited: 7 English Article YM223 BIOCHEM PHARMACOL