Abstract
Background: The androgen receptor (AR) signaling pathway has been well demonstrated to play a crucial role in the development, progression, and drug resistance of prostate cancer. Although the current anti-androgen therapy could significantly benefit prostate cancer patients initially, the efficacy of the single drug usually lasts for a relatively short period, as drug resistance quickly emerges. Methods: We have performed an unbiased bioinformatics analysis using the RNA-seq results in 22Rv1 cells to identify the cell response toward Dip G treatment. The RNA-seq results were validated by qRT-PCR. Protein levels were detected by western blot or staining. Cell viability was measured by Aquabluer and colony formation assay. Results: Here, we identified that Diptoindonesin G (Dip G), a natural extracted compound, could promote the proteasome degradation of AR and polo-like kinase 1 (PLK1) through modulating the activation of CHIP E3 ligase. Administration of Dip G has shown a profound efficiency in the suppression of AR and PLK1, not only in androgen-dependent LNCaP cells but also in castration-resistant and enzalutamide-resistant cells in a CHIP-dependent manner. Through co-targeting the AR signaling, Dip G robustly improved the efficacy of HSP90 inhibitors and enzalutamide in both human prostate cancer cells and in vivo xenograft mouse model. Conclusions: Our results revealed that Dip G-mediated AR degradation would be a promising and valuable therapeutic strategy in the clinic.
Original language | English |
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Pages (from-to) | 917-932 |
Number of pages | 16 |
Journal | Prostate |
Volume | 82 |
Issue number | 8 |
DOIs | |
State | Published - Jun 1 2022 |
Bibliographical note
Publisher Copyright:© 2022 Wiley Periodicals LLC.
Keywords
- CHIP E3 ligase
- Diptoindonesin G
- androgen receptor
- drug resistance
- prostate cancer
ASJC Scopus subject areas
- Oncology
- Urology