Androgen-receptor signalling in normal prostate and PCa

Androgen-receptor signalling in normal prostate and PCa. Free (unbound) testosterone crosses the plasma membrane phospholipid layer presumably by simple diffusion (reaction 1). Once inside the prostate cell, testosterone undergoes metabolism by the 5α-reductase enzyme to produce the more potent androgen 5α-DHT (reaction 2). 5α-DHT binds to the androgen receptor (AR) and causes the AR to undergo activation and transformation, which involves dissociation from heat-shock proteins and conformational (dimerisation) and biochemical changes such as phosphorylation (reaction 3 and 4). The activated and transformed 5α-DHT.AR complex translocates into the nucleus (reaction 5) and interacts with the androgen response element. The 5α-DHT.AR complex binds to the specific DNA response elements (reaction 6) leading to recruitment of coactivators or corepressors to regulate gene expression (reaction 7). We postulate that in the normal prostate, the activation of AR results in downregulation of the expression of the epidermal growth factor receptor (EGFR) mRNA (reaction 7), resulting in reduced EGFR protein synthesis (reaction 8) and the ultimate reduction of the active functional protein (reaction 9). In PCa, we propose that either a molecular switch is turned off along this pathway, probably in regulating gene expression (reaction 7; denoted by +blue colour), resulting in increased mRNA synthesis and increased protein synthesis and increased density of the functional EGFR (reactions 8 and 9). Further, in PCa, activation of EGFR by EGF results in signalling through a host of biochemical pathways (reactions 10–13), which result in activation of AR even in the absence of 5α-DHT. Such a switch in EGFR expression and functional activity results in tumour androgen independence. The loss of androgen regulation concomitant with increased EGFR expression or signalling in PCa through the PI3K and MAPK pathways results in androgen independence of tumour growth. These signalling pathways may activate the AR without ligand, culminating in androgen-receptor signalling, leading to cellular proliferation, migration, and survival. The references for the reactions cited in are as follows: Reaction 1, ; Reaction 2, ; Reaction 3, ; Reaction 4, ; Reaction 5, ; Reaction 6, ; Reaction 7, ; ; ; ; ; ; ; Reaction 8, ; Reaction 9, ; ; Reaction 10, ; ; ; ; ; ; Reaction 11, ; ; ; ; Reaction 12, ; ; ; ; Reaction 13, ; ; ; ; Reaction 14, ; ; ; . Abbreviations: AKT, protein kinase B; AR, androgen receptor; ARE, androgen response element; 5α-DHT, dihydrotestosterone; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MEK, upstream kinases of mitogen-activated protein kinases; mRNA, messenger RNA; P13K, phosphatidylinositol 3 kinase; STAT3, signal transducer and activator of transcription 3; TK, tyrosine kinase. The colour reproduction of this figure is available on the html full text version of the manuscript.

Publication

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth. (2009) A M Traish, et al. Br J Cancer. 2009 Dec 15;101(12):1949-1956. Figure: F1. All organisms Homo sapiens Mus musculus Rattus norvegicus Drosophila melanogaster

Disease mentions