Possible role of adaptive mutation in resistance to antiandrogen in prostate cancer cells.
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.
Hara
Takahito
T
Pharmacology Research Laboratories I, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka, Japan.
Kouno
Jin
J
Nakamura
Kazuyo
K
Kusaka
Masami
M
Yamaoka
Masuo
M
D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D004259:DNA-Directed DNA Polymerase