1. Analysis of anti-tumor effect and mechanism of GLS1 inhibitor CB-839 in colorectal cancer using a stroma-abundant tumor model.
- Author
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Miyamoto R, Takigawa H, Yuge R, Shimizu D, Ariyoshi M, Otani R, Tsuboi A, Tanaka H, Yamashita K, Hiyama Y, Urabe Y, Ishikawa A, Sentani K, and Oka S
- Subjects
- Humans, Animals, Mice, Female, Cell Line, Tumor, Benzeneacetamides pharmacology, Xenograft Model Antitumor Assays, Male, Stromal Cells metabolism, Stromal Cells pathology, Stromal Cells drug effects, Thiadiazoles pharmacology, Gene Expression Regulation, Neoplastic drug effects, Tumor Microenvironment drug effects, Antineoplastic Agents pharmacology, Middle Aged, Disease Models, Animal, Colorectal Neoplasms pathology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Glutaminase antagonists & inhibitors, Glutaminase metabolism, Glutaminase genetics, Cell Proliferation drug effects, Mice, Inbred BALB C
- Abstract
Background: Glutaminase 1 (GLS1), a key enzyme in glutamine metabolism in cancer cells, acts as a tumor promoter and could be a potential therapeutic target. CB-839, a GLS1-specific inhibitor, was developed recently. Herein, we aimed to elucidate the anti-tumor effects and mechanism of action of CB-839 in colorectal cancer (CRC)., Methods: Using the UCSC Xena public database, we evaluated GLS1 expression in various cancers. Immunostaining for GLS1 was performed on 154 surgically resected human CRC specimens. Subsequently, we examined the GLS1 mRNA expression levels in eight CRC cell lines and evaluated the association between GLS1 expression and CB-839 efficacy. To create a reproducible CRC model with abundant stroma and an allogeneic immune response, we co-transplanted CT26 and stem cells into BALB/c mice and treated them with CB-839. Finally, RNA sequencing of mouse tumors was performed., Results: Database analysis showed higher GLS1 expression in CRC tissues than in normal colon tissues. Clinical samples from 114 of the 154 patients with CRC showed positive GLS1 expression. GLS1 expression in clinical CRC tissues correlated with vascular invasion. CB-839 treatment inhibited cancer cell proliferation depending on GLS1 expression in vitro and inhibited tumor growth and metastasis in the CRC mouse model. RNA sequencing revealed that CB-839 treatment inhibited stromal activation, tumor growth, migration, and angiogenesis. These findings were validated through in vitro and in vivo experiments and clinical specimen analysis., Conclusions: GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment., Competing Interests: Declaration of competing interest No conflicts of interest exist for any of the authors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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