Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential.
Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential.
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DOI：
10.1007/s12672-016-0268-z
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发表时间：
2016-08
影响因子：
3
通讯作者：
Simpson MA
中科院分区：
文献类型：
--
作者：
Zimmer BM;Howell ME;Wei Q;Ma L;Romsdahl T;Loughman EG;Markham JE;Seravalli J;Barycki JJ;Simpson MA
前列腺上皮细胞部分通过失活和消除来控制雄激素的效力和可用性。 UDP-葡萄糖脱氢酶 (UGDH) 催化 UDP-葡萄糖通过 NAD+ 依赖性氧化为 UDP-葡萄糖醛酸，这是前列腺葡萄糖醛酸化酶 UGT2B15 和 UGT2B17 导致雄激素失活的重要前体。 UGDH 表达受到雄激素的刺激，从而增加 UDP-葡萄糖醛酸的产生，并促进 UGT 催化的葡萄糖醛酸化。在这项研究中，我们比较了雄激素依赖性前列腺癌和去势抵抗性前列腺癌的同基因 LNCaP 模型中的葡萄糖醛酸化潜力及其对雄激素介导的基因表达的影响。尽管雄激素-葡萄糖苷酸输出显着降低，但 LNCaP 81 去势抵抗肿瘤细胞表达较高水平的 UGDH、UGT2B15 和 UGT2B17。然而，在这些细胞中，雄激素激活的 UGDH 和 PSA 表达的强度以及 AR 依赖性的 UGT2B15 和 UGT2B17 抑制减弱了数倍。与这些结果一致，在去势抵抗细胞中配体激活的 AR 与 PSA 启动子的结合以及随后的转录激活也显着减少。对 UDP 糖库和 UDP 葡萄糖醛酸生产下游途径的通量的分析表明，这些葡萄糖醛酸化前体代谢物通过蛋白聚糖和糖胺聚糖生物合成途径传导，导致 Notch 1 的表面表达增加。UGDH 的敲低减少了 Notch1 并增加了葡萄糖醛酸产量。总体而言，这些结果支持这样一个模型：在雄激素剥夺期间，UDP-葡萄糖醛酸和其他UDP-糖异常分配到替代途径，通过促进细胞表面蛋白聚糖表达的改变，导致前列腺肿瘤细胞雄激素敏感性的丧失。
Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD+-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate, and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen dependent versus castration resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and PSA expression, as well as the AR-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch 1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression.