• 主页
  • 查找结果
  • Estrogen receptor β upregulates FOXO3a and causes induction of apoptosis through PUMA in prostate cancer.

Estrogen receptor β upregulates FOXO3a and causes induction of apoptosis through PUMA in prostate cancer.

Oncogene (2013-10-01)
P Dey, A Ström, J-Å Gustafsson
摘要

Estrogen receptor β (ERβ) is emerging as a critical factor in understanding prostate cancer biology. Although reduced in prostate cancer above Gleason grade 3, ERβ is a potential drug target at the initial stage of the disease. In human prostate cancer cells, we found that ERβ causes apoptosis by increasing the expression of pro-apoptotic factor p53-upregulated modulator of apoptosis (PUMA), independent of p53, but dependent on the forkhead transcription factor class-O family member, FOXO3a. FOXO3a has previously been shown to induce PUMA after growth factor withdrawal and inhibition of the Akt pathway. Surprisingly, the phosphorylation of FOXO3a remained unchanged, while the mRNA and total protein levels of FOXO3a were increased in response to ERβ expression or treatment of PC3, 22Rv1 and LNCaP cells with the ERβ-specific ligands 3β-Adiol (5α-androstane-3β,17β-diol), DPN (diarylpropionitrile) or 8β-VE2 (8-vinylestra-1,3,5 (10)-triene-3,17β-diol). Knockdown of FOXO3a or ERβ expression abolished the increase of PUMA in response to 3β-Adiol in LNCaP and PC3 cells, suggesting that FOXO3a mediates the apoptotic effect of 3β-Adiol-activated ERβ. Moreover, the ventral prostate of ERβ-/- mice had decreased expression of FOXO3a and PUMA compared with the ERβ+/+ mice, indicating a relationship between ERβ and FOXO3a expression. The regulation of FOXO3a by ERβ in normal basal epithelial cells indicates a function of ERβ in cell differentiation and maintenance of cells in a quiescent state. In addition, the expression of ERβ, FOXO3a and PUMA is comparable and higher in benign prostatic hyperplasia than in prostate cancer Gleason grade 4 or higher, where there is substantial loss of ERβ, FOXO3a and PUMA. We conclude that ERβ induces apoptosis of prostate cancer cells by increasing transcription of FOXO3a, leading to an increase of PUMA and subsequent triggering of apoptosis via the intrinsic pathway involving caspase-9. Furthermore, we conclude that ligands specifically activating ERβ could be useful pharmaceuticals in the treatment of prostate cancer.

材料
货号
品牌
产品描述

Sigma-Aldrich
羟乙基哌嗪乙硫磺酸, ≥99.5% (titration)
Sigma-Aldrich
羟乙基哌嗪乙硫磺酸, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
Sigma-Aldrich
HEPES缓冲溶液, 1 M in H2O
Supelco
苏木精
SAFC
羟乙基哌嗪乙硫磺酸
Sigma-Aldrich
荧光素钠, for fluorescence, free acid
Sigma-Aldrich
苏木精, certified by the Biological Stain Commission
Sigma-Aldrich
羟乙基哌嗪乙硫磺酸, BioUltra, for molecular biology, ≥99.5% (T)
SAFC
羟乙基哌嗪乙硫磺酸
Sigma-Aldrich
羟乙基哌嗪乙硫磺酸, BioXtra, pH 5.0-6.5 (1 M in H2O), ≥99.5% (titration)
Sigma-Aldrich
羟乙基哌嗪乙硫磺酸, BioXtra, suitable for mouse embryo cell culture, ≥99.5% (titration)
荧光素钠, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
羟乙基哌嗪乙硫磺酸, anhydrous, free-flowing, Redi-Dri, ≥99.5%
Supelco
HEPES, Pharmaceutical Secondary Standard; Certified Reference Material