MECHANISM OF WARFARIN ACTION IN PROSTATE CANCER

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-321
Ben Yi Tew, Maya Otto-Duessel, Miaoling He, Sumanta Pal, Tommy Tong, Huiqing Wu and Jeremy Jones*
City of Hope, Duarte, CA
Despite incredible advances in detection and treatment, prostate cancer (PC) remains the second leading cause of cancer death in American men. Retrospective studies have shown that prolonged use of the anticoagulant warfarin reduces the incidence of PC, an effect that is not observed for other cancers. However, there has been little investigation into the molecular mechanism behind this clinical observation. Warfarin is a vitamin K antagonist known to inhibit the activity of vitamin K epoxide reductase (VKOR), a key enzyme in the vitamin K cycle. Reduced vitamin K is used by gamma-glutamyl carboxylase (GGCX) as a co-factor for gamma-carboxylation, an important post-translational modification for several proteins involved in coagulation. Oxidized vitamin K must be recycled to the reduced form by VKOR before it can be reused. We identified warfarin and several other vitamin K antagonists in a high-throughput screen for small molecules that inhibited the conformation change and transcriptional activity of the androgen receptor (AR), which is a key mediator of PC initiation and progression. Preliminary data indicate that AR may be gamma-carboxylated in a VKOR-dependent manner. We also found that warfarin and related compounds, as well as siRNA mediated knock-down of VKOR, inhibit AR activity in non-cancerous cell lines but paradoxically increase AR activity in PC cell lines. Preliminary experiments in mice suggest that warfarin may have the same effect on normal prostate cells in vivo. We also found that VKOR, the target of warfarin, is highly expressed in normal human prostate epithelia but is lost in PC, and that this pattern of expression appears to be unique to PC. Because PC is unique in its dependence on androgen/AR-signaling and warfarin reduces the incidence of PC, but not other cancers, we hypothesize that the inhibition of the vitamin K cycle by warfarin decreases AR activity by regulating its carboxylation in healthy prostate cells, thereby slowing PC initiation.

Nothing to Disclose: BYT, MO, MH, SP, TT, HW, JJ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by NIH K99/R00 CA138711 to JOJ.