LAUSR

It is reported that PR-619 is a deubiquitination enzyme inhibitor that can exert anti-tumor effects on a variety of malignancies. We conducted this study to explore the antitumor effects of PR-619 on chondrosarcoma in vitro and in vivo by using two different classes of human chondrosarcoma cell lines SW-11353 and JJ012. To determine these effects, we measured cell viability (MTT), apoptosis (detection of Annexin V-FITC labeling using flow cytometry) and western blot to evaluate molecules associated with apoptosis and cell stress. In addition, we used a nude mouse xenograft mouse model to determine the effect of PR-619 on tumor growth. As our data revealed, in addition to inducing BAD and activating Capase-7, Caspase-8, and PARP, PR-619 also has a dose-effect that induces cytotoxicity, proliferation restriction, and apoptosis in these human chondrosarcoma cells. PR-619 has also been found to activate endoplasmic reticulum pressure-related molecules (caspase-4 and CHOP) and other stress responses (activation of JNK and c-Jun). We conclusively demonstrated the ability of PR-619 to inhibit tumor growth while achieving minimal general toxicity in a developed xenograft mouse model of chondrosarcoma. Therefore, we conclude that PR-619 exacts an antitumor effect in conjunction with cellular and endoplasmic reticulum pressure in human chondrosarcoma. These findings suggest that PR-619 may provide a novel therapeutic strategy for chondrosarcoma. Citation Format: Kuan-Lin Kuo, Chen-Hsun Hsu, Shih-Ming Liao, Kuo-Yuan Huang. Deubiquitinating enzyme Inhibitor PR-619 inducesendoplasmic reticulum stress-related apoptosisin human chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6128.