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

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

doi:10.3389/fonc.2021.615568

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 via 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 in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

Highlights

With nearly 1,276,106 new cases expected worldwide in 2018, prostate cancer (PCa) represents the second-most frequent type of cancer in men following lung cancer, accounting for almost 7.1% of new cancer cases, and there were 358,989 prostate cancer–related deaths in 2018 around the world according to the GLOBOCAN 2018 [1]
LNCaP, the hormone-sensitive prostate cancer (HSPC) cell line, expresses androgen receptor (AR)-FL, which is sensitive to AR-targeted therapy. 22Rv1, the castration-resistant prostate cancer (CRPC) cell line, expresses both AR-FL and androgen receptor splicing variant 7 (AR-V7), which are resistant to AR-targeted therapy
To further verify the downregulation of AR-FL and AR-V7 via ubiquitin-specific protease 14 (USP14) deubiquitinating activity, we examined the effect of IU1, a selective USP14 inhibitor that inhibits its deubiquitination function, and we found decreased AR-FL and AR-V7 in protein levels but not mRNA levels, which corresponded with results in smallinterfering RNA (siRNA) assays

Summary

Introduction

With nearly 1,276,106 new cases expected worldwide in 2018, prostate cancer (PCa) represents the second-most frequent type of cancer in men following lung cancer, accounting for almost 7.1% of new cancer cases, and there were 358,989 prostate cancer–related deaths in 2018 around the world according to the GLOBOCAN 2018 [1]. Some cases are in advanced stages at the time of their initial diagnosis, in unscreened populations, of which ≥10% appear with metastatic disease at first presentation [2]. Androgen deprivation therapy (ADT) is the basic therapy for PCa. Huaier Inhibits Prostate Cancer Growth majority of cases will progress to the more aggressive stages, or castration-resistant prostate cancer (CRPC), within 3 years, and the average overall survival for metastatic CRPC patients is about 1.5 years [9,10,11]

Methods

Results

Conclusion