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

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.