Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction

Abstract

BackgroundAndrogen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression.MethodsPCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression.ResultsThe natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction.ConclusionsBaicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

Virtual screening by targeting proteolytic sites of furin and TMPRSS2 to propose potential compounds obstructing the entry of SARS-CoV-2 virus into human host cells

“…Betulinic acid and bevirimat are also showed potential to inhibit serine protease-2 activity, and these compounds may be potential to use against SARS-CoV-2 because of their anti -HIV properties. Baicalein is known to suppress the androgen receptor (AR) target genes like TMPRSS2 in prostate cancer (PCa) progression, 63 and its effective binding with at the active site can be a potential target to use against COVID-19. Hesperidin is a flavone glycoside that showed a similar binding characteristic to nafamostat, a TMPRSS2 inhibitor.…”

Kaempferol Promotes Apoptosis While Inhibiting Cell Proliferation via Androgen-Dependent Pathway and Suppressing Vasculogenic Mimicry and Invasion in Prostate Cancer

“…Except the well-documented flutamide, new chemicals appear to show therapeutic effects on prostate cancer cells. In our previous study [10, 11], Cryptotanshinone and Baicalein, structures of which are similar to DHT, were found to suppress androgen receptor-mediated growth in androgen-dependent prostate cancer cells. The structure of kaempferol, similar to Cryptotanshinone or Baicalein, is very close to DHT too (Figure 1).…”

“…Refer to the method in our previous studies [10, 11]. In brief, HEK293 and LNCaP cells lacking of functional AR were transfected with wild-type AR expression plasmid and reporter genes such as pSG5-AR, pSG5-PR, pSG5-GR, MMTV-Luc, and pRL-TK-luc for AR for 24 h. Then, the cells were cocultured with various concentrations of kaempferol in the presence or absence of 1 nM dihydrotestosterone (DHT) (Sigma, USA) and/or 5 μ M hydroxyflutamide (HF) (Sigma, USA) for 24 h. The cells were harvested and assayed for luciferase activity.…”

“…RNA extraction and quantitative real-time PCR analysis were performed according to our previous studies [10, 11]. Briefly, after RNA extraction from cells and reverse transcription, quantitative real-time PCR analyses were performed using the SYBR Green PCR Master Mix Kit (Perkin Elmer, MA, USA) according to the manufacturer's instructions.…”

“…Briefly, after RNA extraction from cells and reverse transcription, quantitative real-time PCR analyses were performed using the SYBR Green PCR Master Mix Kit (Perkin Elmer, MA, USA) according to the manufacturer's instructions. The amplification system and primers for AR, PSA, TMPRSS2, TMEPA1, and β -actin normalization control were identical to previous studies [10, 11].…”