Abstract
Abstract Deubiquitinases (DUBs) act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties which can reverse the process of protein degradation, and further affect or regulate cell metabolism, proliferation and differentiation. As a novel small molecular inhibitor, b-AP15 can specifically inhibit the deubiquitinating activity of 19S regulatory subunit UCHL5(ubiquitin C-terminal hydrolase 5) and USP14(ubiquitin-specific peptidase 14) in cancer cells. In this study, we aimed to check whether b-AP15 have anti-tumor activity in esophageal cancer cells in vitro and try to explore the underling mechanisms. Results: CCK-8 assay, colony formation assay and morphological observation results indicate that b-AP15 can significantly inhibit the proliferation activity of EC1 and Kyse 450 esophageal cancer(EC) cell lines in a concentration-dependent manner in vitro studies. Flow cytometry results show cells were arrested in G2/M phase after being treated with b-AP15. Western blot results show that the expression of G2/M phase related proteins p21, p27 and pWee1 significantly increased while the expression of the G1/S phase marker proteins including cyclinA, cyclinD show no significant change after being treated with b-AP15. FITC annexin V Apoptosis detection kit with PI and Caspase 3 Assay kit results show that b-AP15 treatment can significantly induce apoptosis in two EC cell lines. The results from western blot show that the expression of apoptotic protein c-PARP and c-caspase 3 significantly increased and was dose-dependent. JC-1 flow cytometry analysis show that b-AP15 treatment can significantly decrease mitochondrial membrane potential. All these results suggest that b-AP15 can induce EC cells apoptosis and may play certain role in mitochondrial control of apoptosis signaling pathway. Conclusion: b-AP15 shows a significantly anti-tumor activity in vitro models of ESCC and the results confirm that b-AP15 can inhibit proliferation of EC cell lines by inducing cell-cycle arrest and promoting cell apoptosis. Key words: b-AP15;esophageal cancer;deubiquitylatinase(DUBs);apoptosis; Citation Format: Pei Li, Ping Chen, Xiao-Yu Chen, Jing-Yang Zhang, Bei-Bei Sha, Tao Hu, Yi-Lin Zhang, Ying Du, Zi-Ming Dong. The mechanisms of apoptosis induction by deubiquitylatinase inhibitor b-ap15 in esophageal squamous cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5266. doi:10.1158/1538-7445.AM2017-5266
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