title: Gartanin, an isoprenylated xanthone from the mangosteen fruit (Garcinia mangostana), is an androgen receptor degradation enhancer.
abstract: 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.
  
  
  
  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.
  
  
  
  Gartanin is an isoprenylated xanthone that promotes AR degradation with evidence suggesting this process is critically regulated by the unfolded protein response pathway.
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, USA.
authors.forename: Gongbo
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, USA.
authors.forename: Sakina M
authors.initials: SM
authors.lastname: Petiwala
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, USA.|Institute of Clinical Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, USA.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Won
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago College of Pharmacy, Chicago, USA.|University of Illinois Cancer Center, Chicago, USA.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, USA.|Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago College of Pharmacy, Chicago, USA.|University of Illinois Cancer Center, Chicago, USA.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Johnson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005638:Fruit / Q000737:chemistry*; D029762:Garcinia mangostana / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C000605798:1,3,5,8-tetrahydroxy-2,4-bis(3-methyl-2-butenyl)xanthone; C497249:DDIT3 protein, human; D011944:Receptors, Androgen; D044004:Xanthones; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases
keywords: Androgen receptor; Gartanin; Mangosteen; Prostate cancer; Xanthone