Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer.
Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer.
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孤儿核受体作为去势抵抗性前列腺癌瘤内雄激素生物合成的调节剂
DOI：
10.1038/s41388-021-01737-1
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发表时间：
2021-04
期刊：
影响因子：
8
通讯作者：
Chan FL
中科院分区：
文献类型：
--
作者：
Zhou J;Wang Y;Wu D;Wang S;Chen Z;Xiang S;Chan FL
去势抵抗性前列腺癌（CRPC）几乎总是发生在雄激素剥夺治疗（ADT）后的晚期转移性疾病。通常认为，在多种机制和信号传导途径中，CRPC由雄激素去势水平的ADT治疗患者中雄激素受体（AR）信号传导的再激活显著驱动，至少部分由肿瘤内的雄激素生物合成（也称为瘤内或前列腺内雄激素生物合成）介导。类固醇生成酶，如CYP 11 A1、CYP 17 A1、HSD 3B 1、AKR 1C 3和SRD 5A，对于催化初始底物胆固醇转化为赋予CRPC进展的强效雄激素是必需的。越来越多的证据表明，许多类固醇生成酶在进展环境中上调;然而，对CRPC中这些酶的失调知之甚少。孤儿核受体（ONR）是核受体超家族的成员，其内源性生理配体是未知的，并且其独立于任何生理配体而具有组成性活性。研究证实，除AR外，ONRs可能是前列腺癌，特别是致命性CRPC进展的潜在治疗靶点。早期的研究表明，ONRs在类固醇生成酶基因的转录调控中起着至关重要的作用。值得注意的是，我们和其他人表明，三种不同的ONR，包括肝受体同源物-1（LRH-1，NR 5A 2），类固醇生成因子1（SF-1，AD 4 BP，NR 5A 1）和雌激素相关受体α（ERRα，NR 3B 1），可以通过直接转录调节多种类固醇生成酶促进瘤内雄激素合成来促进CRPC进展。本文综述了目前对CRPC瘤内雄激素生物合成的认识，特别关注ONRs在这一过程中的新作用。
Castration-resistant prostate cancer (CRPC) almost invariably occurs after androgen-deprivation therapy (ADT) for the advanced metastatic disease. It is generally believed that among multiple mechanisms and signaling pathways, CRPC is significantly driven by the reactivation of androgen receptor (AR) signaling in ADT-treated patients with castrate levels of androgen, partially at least mediated by the androgen biosynthesis within the tumor, also known as intratumoral or intraprostatic androgen biosynthesis. Steroidogenic enzymes, such as CYP11A1, CYP17A1, HSD3B1, AKR1C3 and SRD5A, are essential to catalyze the conversion of the initial substrate cholesterol into potent androgens that confers the CRPC progression. Accumulating evidences indicate that many steroidogenic enzymes are upregulated in the progression setting; however, little is known about the dysregulation of these enzymes in CRPC. Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily, of which endogenous physiological ligands are unknown and which are constitutively active independent of any physiological ligands. Studies have validated that besides AR, ONRs could be the potential therapeutic targets for prostate cancer, particularly the lethal CRPC progression. Early studies reveal that ONRs play crucial roles in the transcriptional regulation of steroidogenic enzyme genes. Notably, we and others show that three distinct ONRs, including liver receptor homolog-1 (LRH-1,NR5A2), steroidogenic factor 1 (SF-1, AD4BP,NR5A1) and estrogen-related receptor α (ERRα,NR3B1), can contribute to the CRPC progression by promotion of the intratumoral androgen synthesis via their direct transcriptional regulation on multiple steroidogenic enzymes. This review presents an overview of the current understanding on the intratumoral androgen biosynthesis in CRPC, with a special focus on the emerging roles of ONRs in this process.
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影响因子：
64.5
作者：
Chang KH;Li R;Kuri B;Lotan Y;Roehrborn CG;Liu J;Vessella R;Nelson PS;Kapur P;Guo X;Mirzaei H;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
11.2
作者：
Hofland, Johannes;van Weerden, Wytske M.;de Jong, Frank H.
通讯作者：
de Jong, Frank H.
影响因子：
3.7
作者：
Ehrlund A;Jonsson P;Vedin LL;Williams C;Gustafsson JÅ;Treuter E
通讯作者：
Treuter E
DOI：
10.1073/pnas.1112047108
发表时间：
2011-10-11
影响因子：
11.1
作者：
Benod, Cindy;Vinogradova, Maia V.;Sablin, Elena P.
通讯作者：
Sablin, Elena P.
影响因子：
4.1
作者：
Clyne, CD;Kovacic, A;Simpson, ER
通讯作者：
Simpson, ER