Estrogen receptor beta (ERβ) mediates expression of β-catenin and proliferation in prostate cancer cell line PC-3.
The aim of the present study was to characterize the mechanism underlying estrogen effects on the androgen-independent prostate cancer cell line PC-3. 17β-estradiol and the ERβ-selective agonist DPN, but not the ERα-selective agonist PPT, increased the incorporation of [methyl-(3)H]thymidine and the expression of Cyclin D2, suggesting that ERβ mediates the proliferative effect of estrogen on PC-3 cells. In addition, upregulation of Cyclin D2 and incorporation of [methyl-(3)H]thymidine induced by 17β-estradiol and DPN were blocked by the ERβ-selective antagonist PHTPP in PC-3 cells. Upregulation of Cyclin D2 and incorporation of [methyl-(3)H]thymidine induced by DPN were also blocked by PKF118-310, a compound that disrupts β-catenin-TCF (T-cell-specific transcription factor) complex, suggesting the involvement of β-catenin in the estradiol effects in PC-3 cells. A diffuse immunostaining for non-phosphorylated β-catenin was detected in the cytoplasm of PC-3 cells. Low levels of non-phosphorylated β-catenin immunostaining were also detected near the plasma membrane and in nuclei. Treatment of PC-3 cells with 17β-estradiol or DPN markedly increased non-phosphorylated β-catenin expression. These effects were blocked by pretreatment with the ERβ-selective antagonist PHTPP, PI3K inhibitor Wortmannin or AKT inhibitor MK-2206, indicating that ERβ-PI3K/AKT mediates non-phosphorylated β-catenin expression. Cycloheximide blocked the DPN-induced upregulation of non-phosphorylated β-catenin, suggesting de novo synthesis of this protein. In conclusion, these results suggest that estrogen may play a role in androgen-independent prostate cancer cell proliferation through a novel pathway, involving ERβ-mediated activation of β-catenin.
Section of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de maio 100, INFAR, Vila Clementino, São Paulo, SP, 04044-020, Brazil.
Ana Paola G
AP
Lombardi
Section of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de maio 100, INFAR, Vila Clementino, São Paulo, SP, 04044-020, Brazil.
Raisa
R
Pisolato
Section of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de maio 100, INFAR, Vila Clementino, São Paulo, SP, 04044-020, Brazil.
Carolina M
CM
Vicente
Section of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de maio 100, INFAR, Vila Clementino, São Paulo, SP, 04044-020, Brazil.
Maria Fatima M
MF
Lazari
Section of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de maio 100, INFAR, Vila Clementino, São Paulo, SP, 04044-020, Brazil.
Thaís F G
TF
Lucas
Section of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Três de maio 100, INFAR, Vila Clementino, São Paulo, SP, 04044-020, Brazil. Electronic address: csporto@unifesp.br.
Catarina S
CS
Porto
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2 / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D006801:Humans; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D011422:Propionates
D019938:Cyclin D1; D056742:Cyclin D2; D003513:Cycloheximide; D004958:Estradiol; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013936:Thymidine; D051176:beta Catenin; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C556295:4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
Cyclin D2; ERβ; Prostate cancer cells; β-catenin