Ganoderic acid T, a Ganoderma triterpenoid, modulates the tumor microenvironment and enhances the chemotherapy and immunotherapy efficacy through downregulating galectin-1 levels

被引：2

作者：

Chen, Suyu ^{[1
]}

Chen, Kuangdee ^{[1
]}

Lin, Yihsiu ^{[1
]}

Wang, Ssuchia ^{[1
]}

Yu, Huichuan ^{[1
]}

Chang, Chaohsuan ^{[1
]}

Cheng, Tingchun ^{[1
]}

Hsieh, Chiaoyun ^{[1
]}

Li, Jiayi ^{[1
]}

Lai, Hsiaohsuan ^{[1
]}

Chen, Denghai ^{[1
]}

Huang, Chengpo ^{[1
]}

机构：

[1] Trineo Biotechnol Co Ltd, 20F,81,Sec1,Xintai 5th Rd, New Taipei City 221, Taiwan

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2024年 / 491卷

关键词：

Ganoderic acid T; Galectin-1; Anti-cancer; Tumor microenvironment; Immunotherapy; IN-VITRO; CANCER; PACLITAXEL; QUANTIFICATION; COMBINATION; EXPRESSION; APOPTOSIS; CELLS; MODEL; FOCUS;

D O I：

10.1016/j.taap.2024.117069

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Ganoderic acid T (GAT), a triterpenoid molecule of Ganoderma lucidum, exhibits anti-cancer activity; however, the underlying mechanisms remain unclear. Therefore, in this study, we aimed to investigate the anti-cancer molecular mechanisms of GAT and explore its therapeutic applications for cancer treatment. GAT exhibited potent anti-cancer activity in an ES-2 orthotopic ovarian cancer model in a humanized mouse model, leading to significant alterations in the tumor microenvironment (TME). Specifically, GAT reduced the proportion of alpha-SMA+ cells and enhanced the infiltration of tumor-infiltrating lymphocytes (TILs) in tumor tissues. After conducting proteomic analysis, it was revealed that GAT downregulates galectin-1 (Gal-1), a key molecule in the TME. This downregulation has been confirmed in multiple cancer cell lines and xenograft tumors. Molecular docking suggested a theoretical direct interaction between GAT and Gal-1. Further research revealed that GAT induces ubiquitination of Gal-1. Moreover, GAT significantly augmented the anti-cancer effects of paclitaxel, thereby increasing intratumoral drug concentrations and reducing tumor size. Combined with immunotherapy, GAT enhanced the tumor-suppressive effects of the anti-programmed death-ligand 1 antibody and increased the proportion of CD8+ cells in the EMT6 syngeneic mammary cancer model. In conclusion, GAT inhibited tumor growth, downregulated Gal-1, modulated the TME, and promoted chemotherapy and immunotherapy efficacy. Our findings highlight the potential of GAT as an effective therapeutic agent for cancer.

引用

页数：13