Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including prostate cancer. WIN 55,212-2 (WIN) is a highly potent synthetic cannabinoid that binds to cannabinoid receptors (CB1 and CB2). We have previously demonstrated that WIN significantly reduces prostate cancer cell proliferation, migration, invasion, induces apoptosis, and arrests cells in the G0/G1 phase through a cannabinoid receptor 2 dependent manner. We also determined that these effects were mediated though a pathway involving cell cycle regulators p27, Cdk4, and pRb. The current study aims to examine the role of endoplasmic reticulum (ER) stress in apoptosis and investigates whether this effect is modulated by WIN and the cannabinoid receptors.

In this study, we evaluated the effect of WIN and CB receptors on ER stress induced apoptosis in established prostate cancer cells (DU145, PC3). Cells were treated with WIN, cannabinoid receptor 1 antagonist (AM251), and cannabinoid receptor 2 antagonist (AM630). Cell proliferation was determined using MTS assays. Quantitative PCR was used to examine changes in expression of ER stress related genes, including CHOP, TRIB3, and ATF4. Western blotting will be completed to determine changes in the expression of apoptotic markers after treatment with WIN and cannabinoid antagonists. Further studies are ongoing looking at the use of the ER stress inhibitor, Salubrinal, to determine whether ER stress is vital for WIN-induced apoptosis.

Our results reveal that treatment with 20μM WIN resulted in a significant reduction in the proliferation of DU145 and PC3 cells after 24 h compared to control (p<0.05). In contrast, treatment with 5μM of either AM251 or AM630 did not result in any significant changes in cell proliferation. Quantitative PCR studies revealed significant upregulation of ER stress genes CHOP, TRIB3 and ATF4 in WIN treated cells (p<0.05). Expression of ER stress genes were significantly downregulated after blocking CB1 and CB2 receptors (p<0.05).

Interim results suggest that WIN has significant antitumoral activity and modulates ER stress-induced apoptosis in prostate cancer cells, thus, may offer a novel therapeutic strategy in the treatment of prostate cancer.

Citation Format: Domenica Roberto, Laurence H. Klotz, Vasundara Venkateswaran. Cannabinoid WIN 55,212-2 induces endoplasmic reticulum stress in prostate cancer cells through CB1and CB2receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4805.