Niu Yi-Nong, Wang Kai, Jin Song, Fan Dong-Dong, Wang Ming-Shuai, Xing Nian-Zeng, Xia Shu-Jie
Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Weifang Hospital of Traditional Chinese Medicine, Weifang, China.
Asian J Androl. 2016 Nov-Dec;18(6):913-919. doi: 10.4103/1008-682X.167714.
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.
在一项大型临床试验中，非那雄胺降低了低级别前列腺癌（PCa）的发病率，同时增加了高级别癌症的发生率。非那雄胺是否促进高级别肿瘤的发展仍存在争议。我们证明了成纤维细胞和c-Jun在非那雄胺对PCa异种移植模型的化学预防和治疗作用中的作用。将LNCaP（PC3）细胞或癌细胞与成纤维细胞的重组体植入接受非那雄胺治疗的雄性无胸腺裸鼠体内。评估肿瘤生长、细胞增殖、凋亡、p-Akt和p-ERK1/2。在LNCaP（PC3）单移植模型中，非那雄胺没有改变肿瘤生长。在重组移植模型中，成纤维细胞和c-Jun促进肿瘤生长；非那雄胺诱导LNCaP细胞增殖并抑制PC3细胞凋亡。当c-Jun被敲除时，成纤维细胞和/或非那雄胺不会促进肿瘤生长。非那雄胺在单培养癌细胞中抑制p-Akt和p-ERK1/2，而在有成纤维细胞存在的情况下刺激相同的信号分子。在存在c-Jun-/-成纤维细胞的情况下，p-Akt和p-ERK1/2减少。成纤维细胞和c-Jun促进PCa生长；在有成纤维细胞和c-Jun存在的情况下，非那雄胺通过促进增殖、抑制凋亡和上调促增殖分子途径进一步刺激肿瘤生长。基质-上皮相互作用在非那雄胺对PCa的治疗作用中起关键作用。我们的发现对将非那雄胺用作PCa患者的化学预防或治疗药物具有初步意义。
