Glutamic-pyruvic transaminase 1 deficiency–mediated metabolic reprogramming facilitates colorectal adenoma-carcinoma progression

IF 15.8 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-01-01 DOI:10.1126/scitranslmed.adp9805

Li Xiong, Xin Yang, Huashan Liu, Xianrui Wu, Tanxing Cai, Ming Yuan, Liang Huang, Chi Zhou, Xiaobin Zheng, Wenxin Li, Ziwei Zeng, Shujuan Li, Ping Lan, Liang Kang, Zhenxing Liang

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引用次数: 0

Abstract

The tumorigenesis of colorectal cancer (CRC) often follows the normal-adenoma-carcinoma (N-A-C) sequence. However, the molecular mechanisms underlying colorectal adenoma carcinogenesis remain largely unknown. Here, we analyzed transcriptomic profile changes in normal, advanced adenoma, and carcinoma tissues from patients with CRC, revealing that glutamic-pyruvic transaminase 1 ( GPT1 ) in colorectal tissues was down-regulated during the N-A-C process and correlated with poor CRC prognosis. Mechanistically, GPT1 was transcriptionally activated by Krüppel-like factor 4 (KLF4). GPT1 reprogrammed metabolism and suppressed CRC tumorigenesis in cells and mouse models not only through enzyme-dependent α-ketoglutarate (α-KG) production and WNT signaling inhibition but also through enzyme-independent disruption of the folate cycle through binding with methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L). Furthermore, we identified poliumoside as a GPT1 activator that restrained CRC progression in cells, patient-derived CRC organoids, and patient-derived xenograft (PDX) models of CRC. Our study uncovers a role for GPT1 in CRC tumorigenesis and shows that poliumoside is a potential drug for the prevention and treatment of CRC.

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.