Molecular Biology Laboratory, Meir Medical Center, Kfar Saba, Israel.
Prostate. 2010 Sep 1;70(12):1307-12. doi: 10.1002/pros.21166.
Telomerase, which lengthens telomeres, is normally down-regulated in somatic cells and highly up-regulated in dividing cells, such as malignant cells. Human prostate cancer is androgen dependent. Estrogens, including the synthetic estrogen diethylstilbestrol (DES), are used in prostate cancer treatment to reduce androgen levels via feedback inhibition of the hypothalamic release of luteinizing hormone releasing hormone (LH-RH). DES has also direct anticancer activities, such as apoptosis induction. We investigated in vitro the effect of DES on telomerase activity and on gene expression in the presence and absence of androgens. We used two prostate cancer cell lines: LNCaP (androgen dependent) and PC3 (androgen independent).
LNCaP and PC3 cells were treated with 0.1-1,000 nM testosterone or dihydrotestosterone (DHT) in the presence of DES (25 or 50 microM). Cell telomerase activity and gene expression (mRNA) were measured.
LNCaP: As expected, testosterone and DHT significantly increased telomerase activity and gene expression. However, these effects were inhibited by DES. Contrary to expectations, the combination of DES and testosterone functioned synergistically leading to complete inhibition of telomerase activity. PC3: Testosterone and DHT did not affect telomerase activity and gene expression, whereas DES, in the absence or presence of the androgens, significantly inhibited telomerase activity.
In the present study, we demonstrated the ability of DES to inhibit telomerase in prostate cancer cells. Androgens did not limit the inhibitory effect and even acted synergistically with DES in the LNCaP line. This phenomenon should be considered if telomerase inhibition is part of prostate cancer treatment.
端粒酶可延长端粒，通常在体细胞中受到下调，而在分裂细胞（如恶性细胞）中高度上调。人类前列腺癌依赖雄激素。雌激素，包括合成雌激素己烯雌酚（DES），用于前列腺癌治疗中，通过反馈抑制下丘脑释放黄体生成素释放激素（LH-RH）来降低雄激素水平。DES 还具有直接的抗癌活性，如诱导细胞凋亡。我们研究了 DES 在存在和不存在雄激素的情况下对端粒酶活性和基因表达的体外影响。我们使用了两种前列腺癌细胞系：LNCaP（雄激素依赖性）和 PC3（雄激素非依赖性）。
LNCaP 和 PC3 细胞分别用 0.1-1000nM 的睾酮或二氢睾酮（DHT），并加入 DES（25 或 50μM）进行处理。测量细胞端粒酶活性和基因表达（mRNA）。
LNCaP：正如预期的那样，睾酮和 DHT 显著增加了端粒酶活性和基因表达。然而，这些作用被 DES 抑制。出乎意料的是，DES 与睾酮的联合作用具有协同作用，导致端粒酶活性完全抑制。PC3：睾酮和 DHT 不影响端粒酶活性和基因表达，而 DES 在不存在或存在雄激素的情况下，显著抑制端粒酶活性。
在本研究中，我们证明了 DES 抑制前列腺癌细胞中端粒酶的能力。雄激素并没有限制抑制作用，甚至在 LNCaP 细胞系中与 DES 协同作用。如果端粒酶抑制是前列腺癌治疗的一部分，这种现象应该被考虑。
