Proteasome-independent down-regulation of estrogen receptor-alpha (ERalpha) in breast cancer cells treated with 4,4'-dihydroxy-trans-stilbene.
Treatment of cells with estrogens and several pure ERalpha antagonists rapidly induces down-regulation of the alpha-type estrogen receptor (ERalpha) in the nucleus by mechanisms that are sensitive to the proteasome inhibitors, MG132 and clasto-lactacystin-beta-lactone. Hence, it is believed that these ER ligands induce down-regulation of ERalpha by proteasome-dependent mechanisms, which serve to control both the amount of transcriptional activity and the level of ligand-bound ERalpha in cells. In this study, we observed that treatment of cultured MCF-7 and T47D human breast cancer cells with the low affinity ER ligand, 4,4'-dihydroxy-trans-stilbene (4,4'-DHS), inhibited the transcriptional activity of ERalpha and induced slow and gradual decrease in the amount of ERalpha protein (henceforth referred to as down-regulation of ERalpha). The 4,4'-DHS-induced down-regulation of ERalpha in MCF-7 cells involved a mechanism that was insensitive to the two most specific proteasome inhibitors, clasto-lactacystin-beta-lactone and epoxomycin, but sensitive to MG132 at concentrations exceeding that required for maximal inhibition of the proteasome in MCF-7 cells. Therefore, 4,4'-DHS appears to induce down-regulation of ERalpha by a proteasome-independent mechanism. Here, we present data to show that both 4-OH and 4'-OH are critical for the ability of 4,4'-DHS to induce down-regulation of ERalpha and suggest that 4,4'-DHS provides a useful scaffold for development of novel ERalpha antagonists.
Balan
Kannan V
KV
Department of Pediatrics, Rainbow Babies and Children's Hospital, 11100 Euclid Avenue, Suite 3100, Case Western Reserve University, Cleveland, OH 44106, USA.
Wang
Yongbao
Y
Chen
Siming W
SW
Chen
Jin-Chun
JC
Zheng
Li-Fang
LF
Yang
Li
L
Liu
Zhong-Li
ZL
Pantazis
Panayotis
P
Wyche
James H
JH
Han
Zhiyong
Z
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
D017931:DNA Primers; D047628:Estrogen Receptor alpha; D013267:Stilbenes; D004958:Estradiol; C010118:4,4'-dihydroxystilbene; D046988:Proteasome Endopeptidase Complex