Vitamin K epoxide reductase regulation of androgen receptor activity

Abstract

Long-term use of warfarin has been shown to be associated with a reduced risk of prostate cancer. Warfarin belongs to the vitamin K antagonist class of anticoagulants, which inhibit vitamin K epoxide reductase (VKOR). The vitamin K cycle is primarily known for its role in γ-carboxylation, a rare post-translational modification important in blood coagulation. Here we show that warfarin inhibits the transcriptional activity of the androgen receptor (AR), an important driver of prostate cancer development and progression. Warfarin treatment or knockdown of its target VKOR inhibits the activity of AR both in cell lines and in mouse prostate tissue. We demonstrate that AR can be γ-carboxylated, and mapped the γ-carboxylation to glutamate residue 2 (E2) using mass spectrometry. However, mutation of E2 and other glutamates on AR failed to suppress the effects of warfarin on AR suggesting that inhibition of AR is γ-carboxylation independent. To identify pathways upstream of AR signaling that are affected by warfarin, we performed RNA-seq on prostates of warfarin-treated mice. We found that warfarin inhibited peroxisome proliferator-activated receptor gamma (PPARγ) signaling, which in turn, inhibited AR signaling. Although warfarin is unfit for use as a chemopreventative due to its anticoagulatory effects, our data suggest that its ability to reduce prostate cancer risk is independent of its anticoagulation properties. Furthermore, our data show that warfarin inhibits PPARγ and AR signaling, which suggests that inhibition of these pathways could be used to reduce the risk of developing prostate cancer.

Lipid pathway deregulation in advanced prostate cancer

“…Interestingly, FXR may also further impact on PC via upregulation of PTEN (25) (26)(27)(28)(29)(30). It was also thought to be the case in PC (31), however our work (32) and that of others (33) has challenged this view.…”

“…This suggests that treatment with TZD's at high concentrations is not necessarily resulting in specifically PPARG driven effect and indeed the activation of PPARG in this context may be counterintuitive. Recent work now appears to suggest that PPARG activation may be tumourigenic in PC (32,33), and compounding this with the fact that those suffering type II diabetes are often overweight/obese, then an activation of PPARG by TZD could accelerate tumourigenesis.…”

MLS128 antibody-induced suppression of colon cancer cell growth is mediated by a desmocollin and a 110 kDa glycoprotein

“…To identify peptides derived from 110 kDa proteins, in-gel digestion and mass spectrometric analyses were performed as previously described (15,16). Immunoprecipitation (IP) of 110 kDa GP was carried out and resulting IP samples were subjected to 2-D gel electrophoresis as previously described (14).…”

Use of vitamin K antagonists and risk of prostate cancer: Meta–analysis and nationwide case–control study

“…This finding was followed by observational studies reporting 20–30% reductions in prostate cancer risk with VKA use as well as studies reporting neutral associations . In laboratory studies, VKAs have been demonstrated to inhibit Axl–receptor signaling involved in cell growth regulation and to reduce transcriptional activity of the androgen receptor in prostate cancer cells …”

“…[8][9][10] In laboratory studies, VKAs have been demonstrated to inhibit Axlreceptor signaling involved in cell growth regulation and to reduce transcriptional activity of the androgen receptor in prostate cancer cells. 11,12 Given the conflicting epidemiological findings and the potential implications for development of drugs for prevention or treatment of prostate cancer, we conducted a systematic review of the literature, examined the association between VKA use and prostate cancer risk in a nationwide nested case-control study, and pooled the risk estimates from previous and the present study in a meta-analysis.…”