Gamat Melissa, Malinowski Rita L, Parkhurst Linnea J, Steinke Laura M, Marker Paul C
School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, United States of America.
PLoS One. 2015 Oct 1;10(10):e0139522. doi: 10.1371/journal.pone.0139522. eCollection 2015.
The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.
前列腺是男性附属性腺，可产生精液中的分泌物以促进受精。前列腺的分泌功能依赖于雄激素，尽管雄激素发挥作用的机制仍不清楚。多胺是小的阳离子分子，在DNA转录、翻译和基因调控中起关键作用。多胺生物合成中的限速酶是鸟氨酸脱羧酶，由Odc1基因编码。阉割后前列腺中的鸟氨酸脱羧酶mRNA减少，而给予雄激素后增加。此外，给阉割的雄性小鼠注射睾酮可恢复前列腺分泌活性，而给阉割的雄性小鼠同时注射睾酮和鸟氨酸脱羧酶抑制剂D，L-α-二氟甲基鸟氨酸（DFMO）则不能恢复前列腺分泌活性，这表明多胺是雄激素发挥作用所必需的。迄今为止，尚未有人研究过前列腺发育过程中的多胺，而前列腺发育也是依赖雄激素的。在本研究中，我们发现鸟氨酸脱羧酶蛋白在成年小鼠前列腺腹侧、背外侧和前叶的上皮中表达。在前列腺发育之前，鸟氨酸脱羧酶蛋白也在雄性和雌性胚胎的泌尿生殖窦（UGS）上皮中表达，并且在前列腺上皮芽从UGS中出现时持续表达。在UGS器官培养中使用DFMO抑制鸟氨酸脱羧酶可阻断雄激素诱导前列腺芽的形成，并显著降低雄激素诱导的关键前列腺转录因子Nkx3.1的表达。DFMO还显著降低了发育调节基因Notch1的表达。其他与前列腺发育相关的基因，包括Sox9、Wif1和Srd5a2，不受DFMO影响。这些结果共同表明，Odc1和多胺是雄激素在介导前列腺芽诱导中发挥作用所必需的，并且是包括Notch1和Nkx3.1在内的一部分前列腺发育调节基因表达所必需的。
