Gartanin, an isoprenylated xanthone from the mangosteen fruit (Garcinia mangostana), is an androgen receptor degradation enhancer

• Published in: Molecular nutrition & food research 2016-06, Vol.60 (6), p.1458-1469
• Main Authors: Li, Gongbo, Petiwala, Sakina M., Yan, Miao, Won, Jong Hoon, Petukhov, Pavel A., Johnson, Jeremy J.
• Format: Article
• Language: English
• Subjects: Androgen receptor; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Endoribonucleases - genetics; Endoribonucleases - metabolism; Fruit - chemistry; Garcinia mangostana - chemistry; Gartanin; Humans; Inhibitory Concentration 50; Male; Mangosteen; Models, Molecular; Molecular Structure; Prostate cancer; Prostatic Neoplasms - drug therapy; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; Xanthone; Xanthones - pharmacology
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201600037

Scope Androgen receptor (AR) has been a target of prostate cancer for nearly seven decades. In the last several years there has been an interest in identifying compounds that promote degradation of the androgen receptor. In the present study, gartanin, an isoprentylated xanthone in the mangosteen fruit, was evaluated for enhancing AR degradation, and inducing the unfolded protein response pathway. Methods and results The interaction of gartanin with the ligand‐binding domain was characterized using a fluorescence polarization cell‐free assay and cell‐based FRET assay. Western blot analysis identified modulation of ER stress markers (BiP, PERK, IRE1, and CHOP) along with androgen receptor degradation. A computation simulation was performed to identify possible orientations of gartanin with the ligand‐binding domain. Utilizing a cell‐free and cell‐based FRET assays gartanin was found to interact with the ligand‐binding domain through a solely antagonist interaction. Interestingly, inhibition of CHOP, a critical component of the ER stress pathway, was observed to stabilize AR. Conclusions Gartanin is an isoprenylated xanthone that promotes AR degradation with evidence suggesting this process is critically regulated by the unfolded protein response pathway. Gartanin is a polyphenol isolated from the mangosteen fruit (Garcinia mangostana). This study clarifies the anticancer effects of gartanin in prostate cancer cells. Molecular data demonstrate that the primary target of prostate cancer, androgen receptor, is inhibited in cell‐free and cell‐based experiments. These results along with gartanin interacting with the androgen receptor suggest a new mechanism of action for disrupting prostate cancer.