新异甘草素通过抑制雄激素受体活性对前列腺癌发挥肿瘤抑制作用。

Neoisoliquiritin exerts tumor suppressive effects on prostate cancer by repressing androgen receptor activity.

机构信息

Department of Spinal Surgery, Tianjin Hospital, 406 Jiefang South Road, Tianjin, 300211, China.

State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; Research and Development Center of Tianjin University of Traditional Chinese Medicine, Tianjin International Joint Academy of Biotechnology & Medicine, 300457, Tianjin, China.

出版信息

Phytomedicine. 2021 May;85:153514. doi: 10.1016/j.phymed.2021.153514. Epub 2021 Feb 14.

DOI:10.1016/j.phymed.2021.153514

PMID:33676083

Abstract

BACKGROUND

Prostate cancer (PCa) is a major cause of morbidity and mortality in men in both developed and developing countries. Androgens and the androgen receptor (AR) play predominant roles in the progression of PCa. Neoisoliquiritin (NEO) belongs to the class of licorice (Glycyrrhiza) flavonoids, which have a variety of biological activities including anti-depressant, anti-tumor-promoting, and anti-inflammation properties. Licorice root has cancer chemopreventive effects and has been given to PCa patients as an ingredient of PC-SPES, a commercially available combination of eight herbs. Therefore, we determined if NEO can suppress the proliferation of PCa cells.

PURPOSE

We investigated whether and how NEO exerts its anti-neoplastic activity against PCa.

METHODS

The Cell Counting Kit 8 and flow cytometry were used to evaluate the effects of NEO on the proliferation and cell cycle progression of AR-dependent (LNCaP) and AR-independent (PC3) PCa cells. RNA sequencing was employed to examine the genome-wide changes in responsiveness to NEO in LNCaP cells. Quantitative PCR, Western blotting, docking, chromatin immunoprecipitation, and dual-luciferase reporter assays were conducted to determine the mechanism of action of NEO and its potential cross-talk with AR. A LNCaP xenograft nude mouse model was used to determine the inhibitory effects of NEO on AR-dependent PCa tumors in vivo.

RESULTS

NEO inhibited LNCaP cell proliferation in vitro by inducing G0/G1 phase cell cycle arrest. Conversely, NEO treatment had no effect on PC3 cells. Transcriptomic analysis indicated that AR signaling might be the key target of NEO in preventing PCa. NEO regulated AR-mediated cell growth suppression and AR-sensitized cell cycle arrest in LNCaP cells. NEO also blocked several key steps in the AR signaling pathway, including proposed targeting to the ligand binding pocket of AR by computer modeling, modulating AR-androgen response element DNA-binding activity, inhibiting the expression and transcriptional activity of AR, and suppressing downstream AR signaling.

CONCLUSIONS

NEO negatively regulates AR expression and activity, thus supporting the tumor suppressive role for NEO in AR-dependent PCa.

摘要

背景

前列腺癌（PCa）是发达国家和发展中国家男性发病率和死亡率的主要原因。雄激素和雄激素受体（AR）在 PCa 的进展中起主要作用。新异甘草素（NEO）属于甘草（甘草）类黄酮，具有多种生物活性，包括抗抑郁、抗肿瘤促进和抗炎作用。甘草根具有抗癌化学预防作用，并已作为 PC-SPES 的成分给予 PCa 患者，PC-SPES 是一种市售的八种草药组合。因此，我们确定 NEO 是否可以抑制 PCa 细胞的增殖。

目的

我们研究了 NEO 如何抑制 AR 依赖性（LNCaP）和 AR 非依赖性（PC3）PCa 细胞的抗肿瘤活性。

方法

使用细胞计数试剂盒 8 和流式细胞术评估 NEO 对 AR 依赖性（LNCaP）和 AR 非依赖性（PC3）PCa 细胞增殖和细胞周期进程的影响。RNA 测序用于研究 LNCaP 细胞对 NEO 反应的全基因组变化。进行定量 PCR、Western 印迹、对接、染色质免疫沉淀和双荧光素酶报告基因测定，以确定 NEO 的作用机制及其与 AR 的潜在交叉对话。使用 LNCaP 异种移植裸鼠模型在体内确定 NEO 对 AR 依赖性 PCa 肿瘤的抑制作用。

结果

NEO 通过诱导 G0/G1 期细胞周期停滞，在体外抑制 LNCaP 细胞增殖。相反，NEO 处理对 PC3 细胞没有影响。转录组分析表明，AR 信号可能是 NEO 预防 PCa 的关键靶点。NEO 调节 AR 介导的细胞生长抑制和 AR 敏感的细胞周期阻滞在 LNCaP 细胞中。NEO 还阻断了 AR 信号通路中的几个关键步骤，包括计算机建模建议的配体结合口袋靶向 AR、调节 AR-雄激素反应元件 DNA 结合活性、抑制 AR 的表达和转录活性以及抑制下游 AR 信号。