Unzipping androgen action through ZIP9: a novel membrane androgen receptor.

Abstract

Nearly 5 decades ago, the existence of an androgen receptor (AR) molecule was originally identified by Shutsung Liao at the University of Chicago with concordant findings published by Nicholas Bruchovsky and Jean Wilson (1–3). These seminal studies used rat prostate tissue and specifically described a protein with high affinity for 5 -dihydrotestosterone (DHT) that accumulated in the nucleus upon binding, initiating RNA synthesis and explaining the mode of action for androgens within target cells.Subsequentstudiesbymultiple laboratoriesdetermined that AR regulates the transcription of androgen-responsive genes and plays a pivotal role in male reproductive tract development, sexually dimorphic brain activities, and multiple other target tissues. Importantly, AR has an essential role in prostate carcinogenesis and progression, with blockade of its activity used as a primary therapeutic target. Classical nuclear AR signaling (also known as genomic actions) in target cells involves the diffusion of testosterone through the cell membrane and into the cytoplasm, where it or its metabolite DHT binds to the AR, triggering conformational changes, dissociation from heat shock protein 90, dimerization, and translocation to the cell nucleus. There, the AR complex binds to DNA at androgen-response elements, recruits coregulators, and activates transcription of genes that are then translated into proteins. This classic or genomic mechanism of androgen action is relatively slow, requiring approximately 1–6 hours for alterations in gene transcriptional activity. It is noteworthy that as early as 1975, Liao also described rapid androgen actions occurring within 10 minutes of DHT administration that were independent of RNA synthesis, speculating that “androgens may affect known protein factors or others that are yet to be identified” (4). While research attention remain focused on nuclear steroid receptor signaling pathways, culminating in the cloning of steroid receptor genes in the 1980s, including that for AR (5, 6), evidence began to emerge in the 1990s that androgens are also capable of exerting rapid effects by interacting with AR in the cytoplasm or at the plasma membrane. Membrane-associated ARs were initially described in cell types such as T lymphocytes, monocytes, and osteoblasts to effect influx of calcium (7–9). Subsequent studies found that similar to membrane estrogen receptors, membrane ARs can also interactwithsignalingmolecules torapidlyactivatesignaling pathways, including the MAPK/ERK (10) and focal adhesion kinase 1 (FAK) /phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways (11, 12). ARs along the cell surface have also been shown more recently to regulate actin cytoskeletal reorganization and prostate-specific antigen secretion in prostate cancer cells (13). The genomic AR signaling pathway has long been the standard therapeutic target for prostate cancer, and initially blockade of nuclear AR activity is very effective in slowing prostate tumor growth and progression. However, tumors eventually become resistant to nuclear AR antagonists and resume growth and rapid metastatic progression. Nongenomic androgen signaling represents an alternative focus for the development of potential treatment strategies that could enhance tumor response to antiandrogen treatment, particularly in delaying the development of castrate-resistant prostate cancer (14). Progress on studies of nongenomic androgen signaling in prostate cancer cells has been hampered by the challenges associated with identification of novel membrane ARs in these