1. Academic Validation
  2. Diptoindonesin G antagonizes AR signaling and enhances the efficacy of antiandrogen therapy in prostate cancer

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.
Fengyi Mao 1 Yifan Kong 1 Jinghui Liu 1 Xiongjian Rao 1 Chaohao Li 1 Kristine Donahue 2 Yanquan Zhang 1 Katelyn Jones 1 Qiongsi Zhang 1 Wei Xu 2 Xiaoqi Liu 1 3
Affiliations

Affiliations

  • 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.
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.

Keywords

CHIP E3 ligase; Diptoindonesin G; androgen receptor; drug resistance; prostate cancer.

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