Modulators of estrogen receptor inhibit proliferation and migration of prostate cancer cells

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• 作者：Margherita Piccolella ; Valeria Crippa ; Elio Messi ; Marc J. Tetel ; Angelo Poletti
• 关键词：Raloxifen (PubChem CID ; 46882308) ; Genistein (PubChem CID ; 5280961) ; Curcumin (PubChem CID ; 969516) ; ICI182 ; 780 (fulvestrant ; PubChem CID ; 104741) ; 3尾-Adiol (5alpha-androstane-3beta ; 17beta-diol ; PubChem CID ; 242332)
• 刊名：Pharmacological Research
• 出版年：January, 2014
• 年：2014
• 卷：79
• 期：Complete
• 页码：13-20
• 全文大小：1315 K

文摘

In the initial stages, human prostate cancer (PC) is an androgen-sensitive disease, which can be pharmacologically controlled by androgen blockade. This therapy often induces selection of androgen-independent PC cells with increased invasiveness. We recently demonstrated, both in cells and mice, that a testosterone metabolite locally synthetized in prostate, the 5伪-androstane-3尾, 17尾-diol (3尾-Adiol), inhibits PC cell proliferation, migration and invasion, acting as an anti-proliferative/anti-metastatic agent. 3尾-Adiol is unable to bind androgen receptor (AR), but exerts its protection against PC by specifically interacting with estrogen receptor beta (ER尾).

Because of its potential retro-conversion to androgenic steroids, 3尾-Adiol cannot be used 鈥渋n vivo鈥? thus, the aims of this study were to investigate the capability of four ligands of ER尾 (raloxifen, tamoxifen, genistein and curcumin) to counteract PC progression by mimicking the 3尾-Adiol activity.

Our results demonstrated that raloxifen, tamoxifen, genistein and curcumin decreased DU145 and PC3 cell proliferation in a dose-dependent manner; in addition, all four compounds significantly decreased the detachment of cells seeded on laminin or fibronectin. Moreover, raloxifen, tamoxifen, genistein and curcumin-treated DU145 and PC3 cells showed a significant decrease in cell migration. Notably, all these effects were reversed by the anti-estrogen, ICI 182,780, suggesting that their actions are mediated by the estrogenic pathway, via the ER尾, the only isoform present in these PCs.

In conclusion, these data demonstrate that by selectively activating the ER尾, raloxifen, tamoxifen, genistein and curcumin inhibit human PC cells proliferation and migration favoring cell adesion. These synthetic and natural modulators of ER action may exert a potent protective activity against the progression of PC even in its androgen-independent status.