Abstract 1255: The Mediterranean herb rosemary modulates ER stress proteins to promote androgen receptor degradation in prostate cancer cells

Abstract

Abstract Background: Prostate cancer is one of the most prevalent forms of cancer among men, especially in the United States. Epidemiological studies have shown that consumption of natural dietary phytochemicals helps in prevention of many types of cancers. One such dietary phytochemical, rosemary (Rosmarinus officinalis), widely used in Mediterranean cuisine is well known for its antitumor activities. However, not much is known about the effect of rosemary on pathogenesis of prostate cancer. Androgens play a critical role in progression of prostate cancer and hence androgen receptor has been a target for prostate cancer treatment since a long time. Herein we have examined the effect of rosemary on prostate cancer progression. Specifically we have examined how rosemary promotes endoplasmic reticulum (ER) stress and modulates the activity and expression of androgen receptor (AR). Materials and Methods: Prostate cancer cell lines, 22Rv1 and LNCaP cells, were used for all experiments. Cell proliferation and cell viability were studied using BrdU and MTT assay respectively. Western blotting, ELISA and siRNA were used to determine the association between ER stress and AR degradation. Results: Rosemary inhibited growth and decreased the cell viability of 22Rv1 and LNCaP cells in a dose-dependent manner. The anti-proliferative effect was associated with apoptosis as evidenced by a significant increase in levels of cleaved caspase-3 protein and TUNEL assay. Moreover, upon treatment with rosemary we saw a dose-dependent decrease in expression of AR in 22Rv1 and LNCaP cells along with decreased PSA levels in LNCaP cells. Rosemary induced apoptosis was associated with ER stress as evidenced by up-regulation of ER stress proteins PERK, IRE1, BiP, CHOP, XBP-1 and caspase- 4. ER stress proteins are known to play an important role in folding of misfolded proteins and degrading continuously misfolded proteins. We therefore explored the relationship between ER stress and AR degradation. Interestingly, we observed that AR degradation was dependent on ER stress proteins BiP and CHOP. Conclusion: Rosemary induces ER stress-mediated apoptotic cell death in prostate cancer cell lines, 22Rv1and LNCaP cells, leading to disruption of AR expression. Our data suggests that this Mediterranean dietary phytochemical possess strong anticancer activity and should be evaluated further as potential chemopreventive and/or chemotherapeutic agent for controlling prostate cancer. Citation Format: Sakina M. Petiwala, Saba Berhe, Gongbo Li, Angela G. Puthenveetil, Larisa Nonn, Jeremy J. Johnson. The Mediterranean herb rosemary modulates ER stress proteins to promote androgen receptor degradation in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1255. doi:10.1158/1538-7445.AM2014-1255