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

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.

Trichosanthin induces anti-cancer effects by increasing the penetration of Granzyme B into tumor cells

“…GGA contains four structural functional domains, of which the N-terminal Vps, Hrs and STAM (VHS) domain can bind to DXXLL motifs of cargo proteins and was confirmed in our study to directly interact with TCS [7] . TCS then can competitively inhibit cation-independent mannose 6-phosphate receptors (CI-MPRs), a transmembrane glycoprotein, binding to GGA.…”

“…Our recently published study used pull down assay and identified TCS binds with Golgi-localized, γ-ear containing and Arf-binding proteins (GGA) proteins in HepG2 cells [7] . GGA contains four structural functional domains, of which the N-terminal Vps, Hrs and STAM (VHS) domain can bind to DXXLL motifs of cargo proteins and was confirmed in our study to directly interact with TCS [7] .…”

“…TCS then can competitively inhibit cation-independent mannose 6-phosphate receptors (CI-MPRs), a transmembrane glycoprotein, binding to GGA. And such competitive inhibition increased the accumulation of CI-MPRs on the cell surface, and subsequently improved the permeability of tumor cells to Granzyme B (GrzB), as CI-MPR has been identified as a death receptor for GrzB binding and uptake [7] . GrzB is one of the critical effectors released by cytotoxic T lymphocytes (CTLs) and can induce the apoptosis of target cells.…”

Engineering of Ribosome-inactivating Proteins for Improving Pharmacological Properties

“…TCS mediated Phosphoinositide 3-kinase (PI3K)/Protein kinase B (AKT) pathway and thus enhanced cytotoxicity and apoptosis-inducing activity of an anti-cancer therapy Gemcitabine against non-small cell lung cancer [56]. TCS also enhanced the cell penetration of Granzyme B leading to apoptosis of tumor cells [57]. It was shown that TCS incited autophagy in gastric cancer cells via increasing the level of autophagy protein 5 (ATG5), altering microtubule-associated protein 1A/1B-light chain 3 (LC3) I to LC3 II, inducing reactive oxygen species (ROS) and stimulating nuclear factor kappa-B (NF-κB)/Tumor protein p53 (p53) pathway [58].…”

Remodeling the blood–brain barrier microenvironment by natural products for brain tumor therapy

“…Trichosanthin is also a plant toxin belonging to the family of ribosome-inactivating proteins. It has various biological and pharmacological activities, including anti-tumor and immunoregulatory effects 149 . It has dose-dependent inhibitory effect on the invasion, migration and proliferation of human glioma cells and can induce tumor cell apoptosis by the inhibition of WNT/ β -catenin signal pathways 150 .…”