Guerini Vittoria, Sau Daniela, Scaccianoce Eugenia, Rusmini Paola, Ciana Paolo, Maggi Adriana, Martini Paolo G V, Katzenellenbogen Benita S, Martini Luciano, Motta Marcella, Poletti Angelo
Institute of Endocrinology, University of Milan, Italy.
Cancer Res. 2005 Jun 15;65(12):5445-53. doi: 10.1158/0008-5472.CAN-04-1941.
Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5alpha-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor-independent mechanism. We have shown that the dihydrotestosterone metabolite 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor beta (ERbeta), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERbeta signaling. Very surprisingly, estradiol is not active, suggesting the existence of different pathways for ERbeta activation in prostate cancer cells. Moreover, 3beta-Adiol, through ERbeta, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3beta-Adiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the estrogenic effect of testosterone derivatives (ERbeta-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estradiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3beta-hydroxysteroid dehydrogenases (the enzymes responsible for 3beta-Adiol formation) are strongly correlated with hereditary prostate cancer.
前列腺癌的生长在早期阶段依赖雄激素，通常通过雄激素阻断进行药物调节。然而，雄激素剥夺疗法可能会产生雄激素非依赖性前列腺癌，其特征通常是侵袭性增加。我们发现，5α-还原睾酮衍生物双氢睾酮（最有效的天然雄激素）通过一种不依赖雄激素受体的机制抑制细胞迁移。我们已经表明，双氢睾酮代谢物5α-雄烷-3β,17β-二醇（3β-二醇），一种不与雄激素受体结合，但能有效结合雌激素受体β（ERβ）的类固醇，通过激活ERβ信号传导对前列腺癌细胞迁移产生强大抑制作用。非常令人惊讶的是，雌二醇没有活性，这表明前列腺癌细胞中存在不同的ERβ激活途径。此外，3β-二醇通过ERβ诱导E-钙黏蛋白的表达，E-钙黏蛋白是一种已知能够阻断乳腺癌和前列腺癌细胞转移形成的蛋白质。针对E-钙黏蛋白的短发夹RNA可抵消3β-二醇对前列腺癌细胞迁移的抑制作用。总之，数据表明：（a）循环睾酮可能在前列腺中存在的分解代谢过程下游发挥雌激素样作用；（b）睾酮衍生物的雌激素样作用（依赖ERβ）导致细胞迁移受到抑制，尽管它显然与同一受体上与雌二醇相关的作用不同，并且可能对前列腺癌的侵袭和转移具有保护作用。这些结果也为临床观察提供了一些启示提示编码3β-羟基类固醇脱氢酶（负责3β-二醇形成的酶）的基因改变与遗传性前列腺癌密切相关。
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