Abstract 4521: Investigating bAP15, a new inhibitor of UCHL5/USP14 deubiquitinating enzymes, as a potential treatment for chondrosarcoma: A comprehensive in vivo and in vitro study

Abstract

Abstract Chondrosarcoma, a highly resilient cancer characterized by limited effective treatment options, represents a significant therapeutic challenge. bAP15, a novel inhibitor of deubiquitylating enzymes (DUBs), has emerged as a promising therapeutic agent, exhibiting anti-tumor activity in various cancer models. This study investigated the efficacy of bAP15 against chondrosarcoma in vitro and in vivo. To evaluate bAP15's effects on chondrosarcoma cells, the SW1353 and JJ012 cell lines were employed. Cell viability, apoptosis, and cell cycle progression were assessed using MTT assay and flow cytometry. Western blotting was utilized to analyze apoptosis, cell stress, and endoplasmic reticulum (ER) stress. Additionally, a xenograft mouse model was established to examine the in vivo anti-tumor potential of bAP15. Compared to normal cartilage tissue, chondrosarcoma cells exhibited significantly higher expression of the DUB UCHL5, suggesting its potential involvement in chondrosarcoma development. Treatment with bAP15 effectively induced apoptosis in chondrosarcoma cells by activating caspases and cleaving PARP. Furthermore, bAP15 enhanced ER stress by activating caspase-4 and CHOP. In the xenograft mouse model, bAP15 demonstrated remarkable anti-tumor efficacy with minimal toxicity. These findings highlight the potential of bAP15 as a therapeutic strategy for chondrosarcoma. Its ability to induce ER stress and cell cycle arrest, coupled with its in vivo anti-tumor activity, provides compelling evidence for its further development as a novel treatment option for this challenging cancer. Citation Format: Kuan-Lin Kuo, Fu-Shun Hsu, Shang-Jen Chang, Shih-Ming Liao, Wei-Chou Lin, Tzt-Yao Ke, Tzu-Ting Liu, Kuo-Yuan Huang. Investigating bAP15, a new inhibitor of UCHL5/USP14 deubiquitinating enzymes, as a potential treatment for chondrosarcoma: A comprehensive in vivo and in vitro study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4521.