Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to steroid 5α-reductase inhibitors.
Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to steroid 5α-reductase inhibitors.
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DOI：
10.1002/pros.22694
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发表时间：
2013-09
期刊：
影响因子：
2.8
通讯作者：
Mohler, James L.
中科院分区：
文献类型：
--
作者：
Wu, Yue;Godoy, Alejandro;Azzouni, Faris;Wilton, John H.;Ip, Clement;Mohler, James L.
关键词：
用非那雄胺或度他雄胺阻断5 α-还原酶介导的睾酮转化为二氢睾酮（DHT）是两项前列腺癌预防试验背后的驱动假设。影响细胞内雄激素水平和雄激素受体（AR）信号传导轴的因素需要系统地检查，以充分了解使用这些药物干预的结果。通过免疫组织化学和qRT-PCR研究了5种人前列腺癌细胞系中3种5 α-还原酶同工酶的表达。使用质谱法分析细胞内睾酮和DHT。荧光素酶报告基因测定和AR调节基因用于评估AR活性的调节。前列腺癌细胞能够积累睾酮的水平比在培养基中高15 - 50倍。5 α-还原酶同工酶谱和表达不能预测睾酮转化为DHT的能力。除降低细胞内DHT外，非那雄胺和度他雄胺还能够抑制睾酮摄取。由于DHT的可用性降低，药物治疗后AR活性的抑制通常超过预期反应。维持高细胞内睾酮的能力可能会弥补DHT的不足。非那雄胺或度他雄胺的生物学效应似乎很复杂，可能取决于几个因素的相互作用，包括睾酮周转、DHT产生的酶学、睾酮和DHT互换使用的能力以及细胞对脱靶AR抑制作用的倾向。
Blocking 5α-reductase-mediated testosterone conversion to dihydrotestosterone (DHT) with finasteride or dutasteride is the driving hypothesis behind two prostate cancer prevention trials. Factors affecting intracellular androgen levels and the androgen receptor (AR) signaling axis need to be examined systematically in order to fully understand the outcome of interventions using these drugs. The expression of three 5α-reductase isozymes, as determined by immunohistochemistry and qRT-PCR, was studied in five human prostate cancer cell lines. Intracellular testosterone and DHT were analyzed using mass spectrometry. A luciferase reporter assay and AR-regulated genes were used to evaluate the modulation of AR activity. Prostate cancer cells were capable of accumulating testosterone to a level 15–50 times higher than that in the medium. The profile and expression of 5α-reductase isozymes did not predict the capacity to convert testosterone to DHT. Finasteride and dutasteride were able to depress testosterone uptake in addition to lowering intracellular DHT. The inhibition of AR activity following drug treatment often exceeded the expected response due to reduced availability of DHT. The ability to maintain high intracellular testosterone might compensate for the shortage of DHT. The biological effect of finasteride or dutasteride appears to be complex and may depend on the interplay of several factors, which include testosterone turnover, enzymology of DHT production, ability to use testosterone and DHT interchangeably, and propensity of cells for off-target AR inhibitory effect.
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影响因子：
2.8
作者：
Godoy, Alejandro;Kawinski, Elzbieta;Li, Yun;Oka, Daizo;Alexiev, Borislav;Azzouni, Faris;Titus, Mark A.;Mohler, James L.
通讯作者：
Mohler, James L.
影响因子：
4.8
作者：
Godoy, Alejandro;Watts, Anica;Smith, Gary J.
通讯作者：
Smith, Gary J.
影响因子：
1.4
作者：
Azzouni F;Godoy A;Li Y;Mohler J
通讯作者：
Mohler J
影响因子：
2.9
作者：
FALLER, B;FARLEY, D;NICK, H
通讯作者：
NICK, H
影响因子：
4.8
作者：
Askew, Emily B.;Gampe, Robert T., Jr.;Wilson, Elizabeth M.
通讯作者：
Wilson, Elizabeth M.