Antiandrogens Act as Selective Androgen Receptor Modulators at the Proteome Level in Prostate Cancer Cells*

Abstract

Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses dependent upon cellular context.

A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

“…AR protein levels are influenced by antiandrogen treatment [ 50 ]. In accordance with a previous study, the unaltered AR mRNA levels suggest that antiandrogens do not affect AR expression, but rather AR protein turnover, as AR stability [ 25 ].…”

The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

“…In the case of prostate cancer, active AR promotes tumour growth and so treatment options for prostate cancer often target this signalling axis, through the use of androgen deprivation and hormonal therapies such as antiandrogens 27 , 28 . Antiandrogens (e.g., bicalutamide (BIC) and enzalutamide (ENZA)) interact with the AR in the ligand binding pocket and hold the receptor in an inactive conformation, unable to form an active transcriptional complex, and thus inhibit its activity 29 . Importantly, previous studies have demonstrated that the AR is expressed in the lung 30 and studies using mice have confirmed that AR is functional in this organ 31 , 32 .…”

The Effects of Endocrine Disrupting Chemicals on Biomarkers of Inflammation Produced by Lipopolysaccharide Stimulated RAW264.7 Macrophages

“…The combined treatment of flutamide with DHT reversed the inhibition of inflammatory biomarker secretion by RAW264.7 cells. This is probably because flutamide is a selective antagonist of the AR [38]. A similar inhibition response in macrophage RAW264.7 cells culture might be induced by environmental androgenic pollutants.…”