AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer cells

作者：Streicher Wolfgang; Zengerling Friedemann; Laschak Martin; Weidemann Wolfgang; Hoepfner Michael; Schrader Andres J; Jentzmik Florian; Schrader Mark; Cronauer Marcus V^*

来源：World Journal of Urology, 2012, 30(3): 333-339.

DOI：10.1007/s00345-012-0842-0

• C-terminally truncated AR
• Castration resistance
• Prostate cancer

A recently identified mechanism allowing prostate cancer (PCa) cells to grow in the absence of androgens is the expression of constitutively active, C-terminally truncated androgen receptor (AR) variants lacking vast parts of the ligand-binding domain. These AR variants termed AR Delta LBD are either products of alternative splicing, point mutations leading to premature stop codons or proteolytic cleavage of the AR. Some controversies exist about the requirement of additional full-length AR for the full transcriptional activity of the AR Delta LBD. On basis of a mutated, C-terminally truncated AR termed Q640X, we developed an experimental model for the study of AR Delta LBD in PCa cells. %26lt;br%26gt;Activation of AR-dependent promoters was analyzed by reporter gene assays. Dimerization studies were conducted using a mammalian two-hybrid system. %26lt;br%26gt;Although Q640X/Q640X homodimers were able to induce the expression of certain AR target genes, Q640X/AR heterodimers were necessary to activate the full panel of androgen-dependent genes under androgen-deprived conditions. %26lt;br%26gt;The following study supports the hypothesis that castration-resistant prostate cancer (CRPC) cells are able to activate specific androgen-dependent genes by selective modulation of the ratio between AR Delta LBD and their putative dimerization partners like the full-length AR or other AR Delta LBD in the absence of androgens. The present data suggest that AR-mutant Q640X is a powerful experimental tool for the functional analysis of AR Delta LBD in CRPC.

• 出版日期2012-6