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

• Published in: Oncogene Vol. 33; no. 33; pp. 4213 - 4225
• Main Authors: Dey, P, Ström, A, Gustafsson, J-Å
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-08-2014; Nature Publishing Group
• Subjects: 631/208/200; 631/45/612/822; 631/80/82/23; 692/699/67/589/466; AKT protein; Animals; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Care and treatment; Caspase-9; Cell Biology; Cell differentiation; Cell Line, Tumor; Epithelial cells; Estrogen; Estrogen Receptor beta - physiology; Estrogen receptors; Estrogens; Forkhead Box Protein O3; Forkhead protein; Forkhead Transcription Factors - metabolism; FOXO3 protein; Gene Expression Regulation, Neoplastic; Genetic aspects; Human Genetics; Humans; Hyperplasia; Internal Medicine; Ligands; Male; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mice, Nude; Neoplasm Grading; Neoplasm Transplantation; Oncology; original-article; p53 Protein; Phosphorylation; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins - metabolism; Receptors; Therapeutic targets; Tumor Suppressor Protein p53 - metabolism; Up-Regulation; apoptosis; FOXO3a; ERβ; PUMA; p53
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/onc.2013.384

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.