Diptoindonesin G antagonizes AR signaling and enhances the efficacy of antiandrogen therapy in prostate cancer
- Prostate. 2022 Jun;82(8):917-932. doi: 10.1002/pros.24336.
- 1. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA.
- 2. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
- 3. Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
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.