Trichosanthin increases Granzyme B penetration into tumor cells by upregulation of CI-MPR on the cell surface

// Chunman Li 1 , Meiqi Zeng 1 , Huju Chi 1 , Jing Shen 2 , Tzi-Bun Ng 3 , Guangyi Jin 4 , Desheng Lu 4 , Xinmin Fan 4 , Bilian Xiong 1 , Zhangang Xiao 2 , Ou Sha 1 1 Department of Anatomy, Histology and Developmental Biology, School of Basic Medical Sciences, Shenzhen University Health Science Centre, Shenzhen, Guangdong, China 2 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China 3 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China 4 School of Basic Medical Sciences, Shenzhen University Health Science Centre, Shenzhen, Guangdong, China Correspondence to: Ou Sha, email: shaou@szu.edu.cn Zhangang Xiao, email: xzg555898@hotmail.com Keywords: trichosanthin, granzyme B (GrzB), cation-independent mannose-6-phosphate receptor, tumor cells, immunotherapy Received: December 23, 2016      Accepted: February 08, 2017      Published: February 19, 2017 ABSTRACT Trichosanthin is a plant toxin belonging to the family of ribosome-inactivating proteins. It has various biological and pharmacological activities, including anti-tumor and immunoregulatory effects. In this study, we explored the potential medicinal applications of trichosanthin in cancer immunotherapy. We found that trichosanthin and cation-independent mannose-6-phosphate receptor competitively bind to the Golgi-localized, γ-ear containing and Arf-binding proteins. It in turn promotes the translocation of cation-independent mannose-6-phosphate receptor from the cytosol to the plasma membrane, which is a receptor of Granzyme B. The upregulation of this receptor on the tumor cell surface increased the cell permeability to Granzyme B, and the latter is one of the major factors of cytotoxic T lymphocyte-mediated tumor cell apoptosis. These results suggest a novel potential application of trichosanthin and shed light on its anti-tumor immunotherapy.