title: Anti-proliferative activities of finasteride in benign prostate epithelial cells require stromal fibroblasts and c-Jun gene.
abstract: This study aimed to identify the role of mouse fibroblast-mediated c-Jun and IGF-1 signaling in the therapeutic effect of finasteride on benign prostatic epithelial cells. BPH-1 cells, alone or with fibroblasts (c-Jun+/+ or c-Jun-/-), were implanted subcutaneously in male nude mice who were then treated with finasteride. The degrees of cell proliferation, apoptosis, and sizes of the xenografts were determined. BPH-1 cells were grown alone or co-cultured with mouse fibroblasts in the presence of finasteride and the level of IGF-1 secreted into the medium by the fibroblasts was determined. The proliferation-associated signaling pathway in BPH-1 cells was also evaluated. Fibroblasts and c-Jun promoted xenograft growth, stimulated Ki-67 expression, and inhibited BPH-1 apoptosis. Finasteride did not induce the shrinkage of xenografts in the combined-grafted groups despite repressing Ki-67 expression and inducing cell apoptosis. The addition of c-Jun-/- fibroblasts did not promote xenograft growth. In the absence of c-Jun and fibroblasts, finasteride did not alter xenograft growth, Ki-67 expression, or cell apoptosis. The in vitro results demonstrated that when BPH-1 cells were grown in monoculture, treatment with finasteride did not induce cell death and stimulated the expression of pro-proliferative signaling molecules, while in the presence of fibroblasts containing c-Jun, finasteride treatment repressed epithelial cell proliferation, the level of IGF-1 in the medium, and the activation of downstream pro-proliferative signaling pathways. Taken together, our results suggest that fibroblasts, c-Jun, and IGF-1 play key roles in mediating stromal-epithelial interactions that are required for the therapeutic effects of finasteride in benign prostate epithelial cells.
authors.affiliation: Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.|Department of Urology, Weifang Hospital of Traditional Chinese Medicine, Weifang, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Fan
authors.affiliation: Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Mingshuai
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Nianzeng
authors.initials: N
authors.lastname: Xing
authors.affiliation: Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Yinong
authors.initials: Y
authors.lastname: Niu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018120:Finasteride / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016758:Genes, jun; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; D018120:Finasteride; D007334:Insulin-Like Growth Factor I