Possible role of adaptive mutation in resistance to antiandrogen in prostate cancer cells

被引：29

作者：

Hara, T ^{[1
]}

Kouno, J ^{[1
]}

Nakamura, K ^{[1
]}

Kusaka, M ^{[1
]}

Yamaoka, M ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Pharmacol Res Labs 1, Yodogawa Ku, Osaka, Japan

来源：

PROSTATE | 2005年 / 65卷 / 03期

关键词：

adaptive mutation; androgen receptor; antiandrogen; hypermutation; prostate cancer;

D O I：

10.1002/pros.20282

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND. Some mutations of androgen receptor (AR) confer resistance to antiandrogen to prostate cancer (PC) cells. Previously we reported that LNCaP-cxD2 cells established from androgen-dependent LNCaP-FGC PC cells as an antiandrogen bicalutamide-resistant subline harbor W741C/L mutation in the AR gene. In this report, we examined one possible mechanism of the resistance. METHODS. Change in the gene expression and the protein levels relevant to mutagenesis in LNCaP-FGC cells during bicalutamide-treatment was assessed. The AR sequence of bicalutamide-resistant LNCaP-cxD2 cells was compared with that of parental LNCaP-FGC cells. RESULTS. The expression of DNA polymerases (Pol) switched from high-fidelity subset to error-prone subset, and DNA mismatch repair proteins (MMR) were down-regulated. The rate of multiple mutations in the AR gene was higher in LNCaP-cxD2 cells than LNCaP-FGC cells. CONCLUSIONS. These results suggest the hypermutational state might occur in LNCaP-FGC cells during bicalutamide-treatment, which might create the W741C/L mutant AR leading to bicalutamide-resistance.

引用

页码：268 / 275

页数：8

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