# Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer

> **NIH NIH R37** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $371,677

## Abstract

PROJECT SUMMARY
Clinically there are examples of small molecules including finasteride and dutasteride that can reduce the risk of
prostate cancer and potentially may be effect in minimal low risk disease. AR targeting drugs can prove
extremely beneficial for a patient, however, the benefit is short as many of these agents are only effective for
approximately 1 year. In our data collected during the initial 5-year R37 MERIT award we are characterizing
the AR degradation properties of α-mangostin against known AR polymorphisms associated with resistance.
Briefly, PC3 cells were transfected with AR constructs expressing the following Polymorphisms including E256K,
T818D, and T878A. A second biological target for prostate cancer we have evaluated during the initial 5-year
R37 MERIT award was the role of binding immunoglobulin protein (BiP), also known as GRP78 or HSP70. Our
central hypothesis is that xanthones including α-Mangostin from the mangosteen are SARDs that promote
proteolytic degradation of the AR and this mechanism is critically regulated by the multi-functional chaperone
protein BiP. Furthermore, the multi-functional BiP protein in addition to promoting AR degradation is able to
serve as a receptor on the cell surface for the apoptotic ligand Isthmin-1. Importantly, we have observed that
benign prostate epithelial cells when treated with alpha-mangostin do not increase the UPR pathway or the
expression of BiP [2, 4]. Our objective in this proposal is identify opportunities to exploit the multi-functional
properties of BiP that are involved in AR degradation and receptor properties of BiP when localized to the cell
surface involved in apoptosis using xanthones and recombinant Ishthmin-1. Our objective herein will be to
identify key domains of BiP that bind to AR in prostate cancer cells involved in AR degradation. A second
objective will be to functionally characterize the interaction BiP and Isthmin-1 in prostate cancer in combination
with xanthones from the mangosteen fruit. Our third objective will be to optimize the pro-apoptotic properties of
the BiP ligand Isthmin-1 in combination with isoprenylated xanthones.

## Key facts

- **NIH application ID:** 10733300
- **Project number:** 4R37CA227101-06
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jeremy James Johnson
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $371,677
- **Award type:** 4N
- **Project period:** 2019-01-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10733300

## Citation

> US National Institutes of Health, RePORTER application 10733300, Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer (4R37CA227101-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10733300. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*