title: The intriguing role of fibroblasts andc-Junin the chemopreventive and therapeutic effect of finasteride on xenograft models of prostate cancer.
abstract: In a large clinical trial, finasteride reduced the rate of low-grade prostate cancer (PCa) while increasing the incidence of high-grade cancer. Whether finasteride promotes the development of high-grade tumors remains controversial. We demonstrated the role of fibroblasts and c-Jun in chemopreventive and therapeutic effect of finasteride on xenograft models of PCa. LNCaP (PC3) cells or recombinants of cancer cells and fibroblasts were implanted in male athymic nude mice treated with finasteride. Tumor growth, cell proliferation, apoptosis, p-Akt, and p-ERK1/2 were evaluated. In LNCaP (PC3) mono-grafted models, finasteride did not change the tumor growth. In recombinant-grafted models, fibroblasts and c-Jun promoted tumor growth; finasteride induced proliferation of LNCaP cells and repressed PC3 cell apoptosis. When c-Jun was knocked out, fibroblasts and/or finasteride did not promote the tumor growth. Finasteride inhibited p-Akt and p-ERK1/2 in mono-culture cancer cells while stimulating the same signaling molecules in the presence of fibroblasts. Reduced p-Akt and p-ERK1/2 were noted in the presence of c-Jun-/- fibroblasts. Fibroblasts and c-Jun promote PCa growth; finasteride further stimulates tumor growth with promoted proliferation, repressed apoptosis, and up-regulated pro-proliferative molecular pathway in the presence of fibroblasts and c-Jun. Stromal-epithelial interactions play critical roles in finasteride's therapeutic effects on PCa. Our findings have preliminary implications in using finasteride as a chemopreventive or therapeutic agent for PCa patients.
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Yi-Nong
authors.initials: YN
authors.lastname: Niu
authors.affiliation: Weifang Hospital of Traditional Chinese Medicine, Weifang, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Fan
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Ming-Shuai
authors.initials: MS
authors.lastname: Wang
authors.affiliation: Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
authors.forename: Nian-Zeng
authors.initials: NZ
authors.lastname: Xing
authors.affiliation: Department of Urology, Shanghai First Hospital, Jiao Tong University, Shanghai, China.
authors.forename: Shu-Jie
authors.initials: SJ
authors.lastname: Xia
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism*; D018120:Finasteride / Q000494:pharmacology / Q000627:therapeutic use*; D016758:Genes, jun / Q000502:physiology*; D064593:Heterografts; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D018120:Finasteride; D051057:Proto-Oncogene Proteins c-akt