Bombinin-BO1 induces hepatocellular carcinoma cell-cycle arrest and apoptosis via the HSP90A-Cdc37-CDK1 axis
Xiaoting Wang,
Peiyu Tang,
Yitong Gong,
Hang Yao,
Mingpeng Liang,
Hongxia Qu,
Xiao Han,
Qiusheng Zheng,
Zhen Shi,
Defang Li,
Qingling Jiang
Affiliations
Xiaoting Wang
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
Peiyu Tang
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
Yitong Gong
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; School of Basic Medical Sciences, Binzhou Medical University, Yantai 264003, Shandong, P.R. China
Hang Yao
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
Mingpeng Liang
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
Hongxia Qu
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
Xiao Han
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
Qiusheng Zheng
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
Zhen Shi
School of Basic Medical Sciences, Binzhou Medical University, Yantai 264003, Shandong, P.R. China; Corresponding author
Defang Li
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Corresponding author
Qingling Jiang
Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Collaborative Innovation Platform for Modernization and Industrialization of Regional Characteristic Traditional Chinese Medicine, School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China; Corresponding author
Summary: Bombinin-BO1 (BO1), a bombinin peptide derived from the skin secretion of Bombina orientalis, exhibits broad-spectrum antimicrobial activity. To date, the anticancer effect of BO1 remains unclear. This study confirmed cytotoxicity of BO1 on hepatocellular carcinoma cells by inducing S-phase cycle block and apoptosis. In addition, BO1 was found to be localized in cytoplasm through endocytosis. The combined results of pull down, mass spectrometry, and co-immunoprecipitation suggested that BO1 induced misfolding of CDK1 and degradation by competitively binding HSP90A with Cdc37. It was verified that overexpression of HSP90A in BO1-treated cells significantly inhibited degradation of CDK1. In vivo, BO1 inhibited tumor without being toxic to individuals. This study reveals the anti-tumor mechanism of BO1 in inducing cell-cycle arrest and apoptosis by interfering with HSP90A-Cdc37-CDK1 system. This is the first study to analyze the mechanism of BO1 regulation of tumor cells, providing theoretical basis for BO1 treatment of hepatocellular carcinoma.
