Abstract 3238: A novel natural product disrupts androgen receptor signaling in prostate cancer cells.

Abstract

Abstract Continued reliance on androgen receptor (AR) signaling is a hallmark of prostate cancer, including the development of castration-resistant prostate cancer (CRPC), making it an attractive therapeutic target for prostate cancer treatment. Mahanine is a novel carbazole alkaloid derived from the leaves of Murraya koenigii, commonly known as the curry leaf plant, which grows widely across East Asia. We have reported previously that mahanine possesses the ability to inhibit prostate cancer cell growth. Since sustained AR signaling is associated with the development of CRPC, we investigated the effect of mahanine treatment on AR signaling in prostate cancer cells. Using reverse transcriptase polymerase chain reaction, we observed that AR signaling was disrupted by mahanine treatment, leading to a prominent decline in the expression of a number of AR target genes. Androgen response element-luciferase and PSA promoter-luciferase assays showed that androgen-induced AR transcriptional activity diminished by approximately 85% upon mahanine treatment. Furthermore, mahanine induced the export of the AR from the nucleus, resulting in its accumulation in the cytoplasm. Cellular levels of the AR were found to decrease in a time- and dose-dependent manner following mahanine treatment, without any noticeable change in its message levels, suggesting that mahanine affected AR protein levels post-translationally, without any effect on its gene expression. Concomitant administration of a proteasome inhibitor, MG132, significantly rescued the decline in AR levels observed upon mahanine treatment, indicating that mahanine induced proteasomal degradation of the AR. Collectively, these data demonstrate that mahanine treatment disrupts AR signaling in prostate cancer cells, leading to its cytoplasmic accumulation and subsequent degradation by proteasomal mechanisms, and suggest a potential therapeutic role for mahanine in prostate cancer treatment. This work is supported by NIH R01 CA131123. Citation Format: Karishma Amin, Shankar Jagadeesh, Nabin Barua, Samir Bhattacharya, Partha P. Banerjee. A novel natural product disrupts androgen receptor signaling in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3238. doi:10.1158/1538-7445.AM2013-3238