Abstract 2625: Proteasome inhibitor Bortezomib increases anti-cancer activity of novel anti-inflammatory anti-androgen Compound A

Abstract

Abstract Signaling by the steroid hormone receptors plays a pivotal role in the development of prostate cancer. Androgens and the androgen receptor (AR) promote prostate tumorigenesis. In contrast, the glucocorticoid receptor (GR) plays tumor suppressive role in the prostate. The major molecular mechanisms underlying GR anti-cancer and anti-inflammatory effects are similar and based on GR transrepression that involves negative interaction between GR and other transcription factors. We anticipated that anti-inflammatory anti-androgens hold a great potential for prostate cancer treatment. Thus, we identified the potential AR/GR ligands with this functional profile by screening of selective GR activators (SEGRA) recently synthesized in USA and Europe as anti-inflammatory GR ligands with reduced side effects. The lead identified compound is Compound A (CpdA), a synthetic analogue of a hydroxyphenyl aziridine precursor isolated from the Namibian shrub Salsola Botschantzev. We and others showed that CpdA inhibits AR function, prevents GR dimerization and transactivation, but strongly enhances GR transrepression. It is known that proteasome inhibitors tightly control GR and AR degradation and function. We show here that the exposure of prostate cancer cells expressing endogenous AR and GR to proteasome inhibitor Bortezomib (BZ) resulted in strong degradation of AR and accumulation of GR. The androgen DHT prevented AR destabilization induced by BZ. In contrast to androgen, CpdA cooperated with BZ to decrease AR expression and function. In addition, BZ modified the functional profile of GR in a ligand-dependent fashion. In the presence of GR modulator CpdA, BZ did not induce GR transactivation but augmented CpdA effect on GR transrepression measured by the inhibition of several transcription factors such as NF-kB, AP-1 and STAT1. Finally we revealed a strong cooperation between CpdA and BZ in activation of apoptosis and endoplasmic reticular stress in prostate cancer cells. Overall, our data suggest that combination of BZ with steroid receptor modulators such as CpdA, has a high potential for PC therapy. Work is supported by RO1CA118890 (to IB) and ACS IL grant #160185 (to AY). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2625.