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槐耳提取物通过靶向AR/AR-V7通路抑制前列腺癌生长。

Huaier Extract Inhibits Prostate Cancer Growth Targeting AR/AR-V7 Pathway.

作者信息

Liu Zhengfang, Liu Cheng, Yan Keqiang, Liu Jikai, Fang Zhiqing, Fan Yidong

机构信息

Department of Urology, Qilu Hospital of Shandong University, Ji'nan, China.

Department of Urology, Peking University Third Hospital, Beijing, China.

出版信息

Front Oncol. 2021 Feb 23;11:615568. doi: 10.3389/fonc.2021.615568. eCollection 2021.

DOI:10.3389/fonc.2021.615568
PMID:33708629
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7940541/
Abstract

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment and models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

摘要

雄激素受体（AR）在前列腺癌发生过程中起关键作用，并且它还影响激素敏感性前列腺癌（HSPC）向去势抵抗性前列腺癌（CRPC）的转变。特别是，雄激素受体的持续激活以及雄激素受体剪接变体7（AR-V7）的出现，可能部分解释了雄激素剥夺治疗（ADT）的失败。在本研究中，我们报道了源自药用真菌的槐耳提取物在HSPC和CRPC细胞中均具有强大的抗增殖作用。从机制上讲，槐耳提取物通过靶向含SET和MYND结构域蛋白3（SMYD3）信号通路下调全长AR（AR-FL）和AR-V7的mRNA水平。槐耳提取物还通过下调蛋白酶体相关的去泛素化酶泛素特异性蛋白酶14（USP14）来增强蛋白酶体介导的AR-FL和AR-V7的蛋白质降解。此外，槐耳提取物抑制AR-FL/AR-V7的转录活性及其核转位。更重要的是，我们的数据表明槐耳提取物可以使恩杂鲁胺耐药的前列腺癌细胞对恩杂鲁胺治疗重新敏感，并建立模型。我们的工作表明，槐耳提取物作为单一疗法或与恩杂鲁胺联合使用对前列腺癌治疗可能有效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/6a79be6ecb7e/fonc-11-615568-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/04d816bac836/fonc-11-615568-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/96d355362fec/fonc-11-615568-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/27a441362dcd/fonc-11-615568-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/316b8cf1b190/fonc-11-615568-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/214d3d79033c/fonc-11-615568-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/0bece6c0b187/fonc-11-615568-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/6a79be6ecb7e/fonc-11-615568-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/04d816bac836/fonc-11-615568-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/96d355362fec/fonc-11-615568-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/27a441362dcd/fonc-11-615568-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/316b8cf1b190/fonc-11-615568-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/214d3d79033c/fonc-11-615568-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/0bece6c0b187/fonc-11-615568-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a408/7940541/6a79be6ecb7e/fonc-11-615568-g007.jpg

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