Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Exp Mol Pathol. 2024 Jun;137:104896. doi: 10.1016/j.yexmp.2024.104896. Epub 2024 May 3.
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).
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.
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.
GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment.
谷氨酰胺酶 1（GLS1）是癌细胞中谷氨酰胺代谢的关键酶，作为一种肿瘤促进剂，可能成为潜在的治疗靶点。最近开发了一种 GLS1 特异性抑制剂 CB-839。在此，我们旨在阐明 CB-839 在结直肠癌（CRC）中的抗肿瘤作用和作用机制。
使用 UCSC Xena 公共数据库，我们评估了各种癌症中的 GLS1 表达。对 154 例手术切除的人 CRC 标本进行 GLS1 免疫染色。随后，我们检测了 8 种 CRC 细胞系中的 GLS1 mRNA 表达水平，并评估了 GLS1 表达与 CB-839 疗效之间的关系。为了创建富含基质和同种异体免疫反应的可重复 CRC 模型，我们将 CT26 和干细胞共移植到 BALB/c 小鼠中，并给予 CB-839 治疗。最后，对小鼠肿瘤进行 RNA 测序。
数据库分析显示 CRC 组织中的 GLS1 表达高于正常结肠组织。154 例 CRC 患者中有 114 例的临床样本显示 GLS1 表达阳性。CRC 临床组织中的 GLS1 表达与血管浸润相关。CB-839 治疗在体外依赖 GLS1 表达抑制癌细胞增殖，并抑制 CRC 小鼠模型中的肿瘤生长和转移。RNA 测序显示 CB-839 治疗抑制基质激活、肿瘤生长、迁移和血管生成。这些发现通过体外和体内实验以及临床标本分析得到了验证。
CRC 中的 GLS1 表达在肿瘤进展中起着重要作用。CB-839 对癌症增殖和肿瘤微环境具有抑制作用。
