Abstract 3929: Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: A novel therapeutic modality
Authors: Yemelyanov Alexander , Bhalla Pankaj , Ugolkov Andrey , Yang Ximing , Budunova Irina 
Published: August 2012

Androgen (AR) and glucocorticoid (GR) receptor signaling play opposing roles in prostate tumorigenesis: in prostate AR acts as an oncogene and GR is a tumor suppressor. Here we explored a novel strategy of simultaneous inhibition of AR and activation of GR signaling for prostate cancer treatment using non-steroidal AR/GR modulator Compound A (CpdA) in combination with proteasome inhibitor Bortezomib (BZ). We and others found that CpdA acts as anti-inflammatory anti-androgen. It inhibits basal and DHT-induced AR activity; does not induce GR dimerization and transactivation but induces GR transrepression via inhibition of several transcription factors, including NF-kB, AP-1, and others. We also previously reported that CpdA has high anti-PC potential (Yemelyanov et al., 2008). It is known that GR and AR are controlled by proteasomal degradation. Here we show that prolonged exposure of prostate carcinoma (PCa) cells PC3 (AR-/GR+), DU145 (AR-/GR+), LNCaP (AR+/GR-), and LNCaP-GR (AR+/GR+), to BZ caused AR degradation and GR accumulation. BZ enhanced CpdA ability to inhibit AR and to augment GR transrepression. We also found that CpdA+BZ cooperatively inhibited PCa cell growth and survival and induced endoplasmic reticulum stress (ERS) as was indicated by up-regulation of BIP/HSPA5, ATF2 phosphorylation and nuclear translocation, and by induction of downstream pro-apoptotic ERS effector CHOP/GADD153. In contrast, glucocorticoid fluocinolone acetate and androgen DHT down-regulated cytoplasmic and nuclear CHOP, pointing to the ability of the androgens and glucocorticoids to counteract ERS in PC cells. Using ChIP we showed that BIP/HSPA5 and CHOP regulation was due to effects of CpdA and CpdA+BZ on GR loading on their promoters. Since CHOP/GADD153 was differentially activated by CpdA and BZ+CpdA via GR, we analyzed its role in anti-cancer effect of CpdA+BZ. The cooperative CpdA+BZ growth suppression and induction of apoptosis were significantly stronger in LNCaP-GR-CHOP compared to LNCaP-GR cells with low endogenous CHOP expression. Growth suppression and apoptosis induction by CpdA+BZ were drastically diminished in LNCaP-GR-shCHOP cells with depleted endogenous CHOP. Finally, we found that AR and GR are abundant in advanced PCa from patients treated by androgen ablation and/or chemotherapy: 56% of carcinomas from treated patients expressed both receptors, and the other 27% expressed either GR or AR. Overall, our data validate the concept of dual AR/GR targeting in prostate cancer (PC), and suggest that BZ combination with dual-target steroid receptor modulator CpdA has high potential for PC therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3929. doi:1538-7445.AM2012-3929