Non-Genomic Actions of the Androgen Receptor in Prostate Cancer

Abstract

Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens. In the canonical pathway, binding of androgen to AR LBD triggers the release of AR from molecular chaperones which enable conformational changes and protein–protein interactions to facilitate its nuclear translocation where it regulates the expression of target genes. However, preceding AR function in the nucleus, initial binding of androgen to AR LBD in the cytoplasm may already initiate signal transduction pathways to modulate cellular proliferation and migration. In this article, we review the significance of signal transduction pathways activated by rapid, non-genomic signaling of the AR during the progression to metastatic CRPC and put into perspective the implications for current and novel therapies that target different domains of AR.

Sex Steroids, Adult Neurogenesis, and Inflammation in CNS Homeostasis, Degeneration, and Repair

“…Estrogen-activation of the GPERs (and likely membrane-associated ERs, as well) initiates PI3K/AKT and MAPK/ERK signaling pathways ( 13 ), that in turn coordinate the transcription and translation of whole gene families that regulate cellular processes including, but not limited, to cellular differentiation, proliferation, survival, and apoptosis ( 14 ). Similarly, androgens and progesterones exert their functional effects on transcription and translation through intracellular canonical genomic signaling and the non-genomic signaling cascades PI3K/AKT and MAPK/ERK ( 15 , 16 ). Differential androgen signaling depends on cytoplasmic- versus membrane-targeted isoforms of the androgen receptor gene ( 16 ).…”

“…Similarly, androgens and progesterones exert their functional effects on transcription and translation through intracellular canonical genomic signaling and the non-genomic signaling cascades PI3K/AKT and MAPK/ERK ( 15 , 16 ). Differential androgen signaling depends on cytoplasmic- versus membrane-targeted isoforms of the androgen receptor gene ( 16 ). By contrast progesterone receptors, like estrogen receptors, are encoded by distinct genes and include the intracellular receptors PR-A and PR-B and the membrane progesterone receptor isoforms alpha (mPRα), beta (mPRβ), and gamma (mPRγ) ( 17 ).…”

Phosphorylation of HSP90 by protein kinase A is essential for the nuclear translocation of androgen receptor

“…Several studies have demonstrated that the AR can be stimulated by high cAMP levels. AR transactivation by androgens could be enhanced by forskolin and other activators of adenylate cyclase in AR-transfected monkey kidney CV-1 cells or PC3 cells (1,12). The increase in AR transcription was caused by enhanced AR-DNA binding and was not due to an increase in AR protein expression (1).…”

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

“…While still in the cytoplasm, AR can bind to several proteins and activates SRC, RAS, MAPK, AKT, EGFR, and PI3K among others Hellen Kuasne and Mateus C. Barros-Filho contributed equally to this work. [7,8]. Non-genomic AR signaling promotes tumor cell survival, proliferation, migration, invasion, and metastasis [9].…”