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

ABSTRACT

Estrogen receptor ß (ERß) is emerging as a critical factor in understanding prostate cancer biology. Although reduced in prostate cancer above Gleason grade 3, ERß is a potential drug target at the initial stage of the disease. In human prostate cancer cells, we found that ERß 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 ERß expression or treatment of PC3, 22Rv1 and LNCaP cells with the ERß-specific ligands 3ß-Adiol (5α-androstane-3ß,17ß-diol), DPN (diarylpropionitrile) or 8ß-VE2 (8-vinylestra-1,3,5 (10)-triene-3,17ß-diol). Knockdown of FOXO3a or ERß expression abolished the increase of PUMA in response to 3ß-Adiol in LNCaP and PC3 cells, suggesting that FOXO3a mediates the apoptotic effect of 3ß-Adiol-activated ERß. Moreover, the ventral prostate of ERß-/- mice had decreased expression of FOXO3a and PUMA compared with the ERß+/+ mice, indicating a relationship between ERß and FOXO3a expression. The regulation of FOXO3a by ERß in normal basal epithelial cells indicates a function of ERß in cell differentiation and maintenance of cells in a quiescent state. In addition, the expression of ERß, 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 ERß, FOXO3a and PUMA. We conclude that ERß 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 ERß could be useful pharmaceuticals in the treatment of prostate cancer.