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

Pulmonary and Respiratory Medicine 0301 basic medicine Ubiquitin-Proteasome Proteolytic Pathway Cell biology Carcinogenesis androgen receptor splicing variant 7 (AR-V7) Cancer research Androgen deprivation therapy 03 medical and health sciences Advancements in Prostate Cancer Research 0302 clinical medicine Biochemistry, Genetics and Molecular Biology Health Sciences Enzalutamide full length androgen receptor (AR-FL) Molecular Biology Biology Internal medicine RC254-282 Cancer Chemotherapy-Induced Peripheral Neuropathy in Cancer Treatment Prostate cancer enzalutamide Proteasome Prostate Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Life Sciences prostate cancer 3. Good health Androgen receptor Chemistry Oncology Androgen Receptor Medicine huaier extract
DOI: 10.3389/fonc.2021.615568 Publication Date: 2021-02-23T05:26:12Z
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.
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