5 α -雄烷-3 α,17 β -二醇选择性激活典型的PI3K/AKT通路:雄激素激活细胞质信号传导的生物信息学证据。

IF 3.5 Q1 EDUCATION & EDUCATIONAL RESEARCH Genomic medicine Pub Date : 2007-01-01 Epub Date: 2008-02-27 DOI:10.1007/s11568-008-9018-9
Mikhail G Dozmorov, Qing Yang, Adam Matwalli, Robert E Hurst, Daniel J Culkin, Bradley P Kropp, Hsueh-Kung Lin
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引用次数: 4

摘要

5 α -雄甾烷-3 α,17 -二醇(3 α -二醇)由强效雄激素5 α -二氢睾酮(5 α - dht)通过还原性3 α -羟基类固醇脱氢酶(3 α - hsds)在前列腺中还原。3 -二醇被认为是一种弱雄激素,对雄激素受体(AR)的亲和力较低,但可以被氧化回5 -二醇二醇。然而,3 α -二醇可能通过激活细胞质信号通路,刺激ar不依赖型前列腺细胞生长,更重要的是,为雄激素不依赖型前列腺癌的进展提供关键信号,从而发挥强大的作用。一种癌症特异性的,基于dna的膜阵列被用来确定3 α -二醇激活的途径在调节前列腺癌细胞存活和/或增殖。LNCaP细胞中的几种典型途径似乎受到3α -二醇调节反应的影响;其中包括凋亡信号通路、PI3K/AKT信号通路和死亡受体信号通路。生物学分析证实,3 -二醇刺激AKT活化;AKT通路可以独立于经典的AR信号而被激活。这些观察结果支持了我们之前的观察结果,即无论AR状态如何,3 - α -二醇都会继续支持前列腺细胞的存活和增殖。我们提供了第一个系统生物学方法来证明3 - α -二醇激活的细胞质信号通路是人类前列腺细胞雄激素激活的生物学功能的重要组成部分。根据观察,在局部和晚期前列腺癌中,还原性3 α - hsd的表达水平显著升高,因此,在雄激素剥夺的情况下,3 α -二醇可能在雄激素依赖型前列腺癌向雄激素非依赖型前列腺癌转变中发挥关键作用。
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5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling.

5alpha-Androstane-3alpha,17beta-diol (3alpha-diol) is reduced from the potent androgen, 5alpha-dihydrotestosterone (5alpha-DHT), by reductive 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs) in the prostate. 3alpha-diol is recognized as a weak androgen with low affinity toward the androgen receptor (AR), but can be oxidized back to 5alpha-DHT. However, 3alpha-diol may have potent effects by activating cytoplasmic signaling pathways, stimulating AR-independent prostate cell growth, and, more importantly, providing a key signal for androgen-independent prostate cancer progression. A cancer-specific, cDNA-based membrane array was used to determine 3alpha-diol-activated pathways in regulating prostate cancer cell survival and/or proliferation. Several canonical pathways appeared to be affected by 3alpha-diol-regulated responses in LNCaP cells; among them are apoptosis signaling, PI3K/AKT signaling, and death receptor signaling pathways. Biological analysis confirmed that 3alpha-diol stimulates AKT activation; and the AKT pathway can be activated independent of the classical AR signaling. These observations sustained our previous observations that 3alpha-diol continues to support prostate cell survival and proliferation regardless the status of the AR. We provided the first systems biology approach to demonstrate that 3alpha-diol-activated cytoplasmic signaling pathways are important components of androgen-activated biological functions in human prostate cells. Based on the observations that levels of reductive 3alpha-HSD expression are significantly elevated in localized and advanced prostate cancer, 3alpha-diol may, therefore, play a critical role for the transition from androgen-dependent to androgen-independent prostate cancer in the presence of androgen deprivation.

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