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激活转录因子4（ATF4）通过转录诱导溶质载体家族1成员5（SLC1A5）促进结直肠癌中的谷氨酰胺分解和糖酵解。

ATF4 promotes glutaminolysis and glycolysis in colorectal cancer by transcriptionally inducing SLC1A5.

作者信息

Zhou Zengli, Ye Shufang, Chen Jingyu, Dai Fei, Chen Luyi, Ye Ran, Zhang Jianmei, Chen Gefei, Wang Yanjiao, Liu Yangyang

机构信息

Department of Gastroenterology, Wenzhou Medical University Lishui Hospital, Lishui People's Hospital, First Affiliated Hospital of Lishui University, Lishui 323000, China.

Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.

出版信息

Acta Biochim Biophys Sin (Shanghai). 2024 Dec 17;57(7):1093-1105. doi: 10.3724/abbs.2024226.

DOI:10.3724/abbs.2024226
PMID:39696988
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12383793/
Abstract

Glutaminolysis and glycolysis promote the malignant progression of colorectal cancer. The role of activating transcription factor 4 (ATF4) in solute carrier family 1 member 5 (SLC1A5)-mediated glutaminolysis and glycolysis remains to be elucidated. SLC1A5 and ATF4 expression levels are detected in colorectal cancer tissues. is knocked down or overexpressed to assess its role in cell viability, migration and invasion. is knocked down to evaluate its role in cell viability, migration, invasion, and metastasis and the metabolism of glutamine and glucose. The regulatory effect of the transcription factor ATF4 on SLC1A5 transcription and expression is determined using a luciferase reporter assay and chromatin immunoprecipitation (ChIP) techniques. Upregulated ATF4 and SLC1A5 expressions are observed in tumor tissue, which is positively correlated with the tumor, node, and metastasis (TNM) stages. overexpressing SW480 cells show the increased cell viability, migration and invasion. Conversely, knockdown decreases the viability, migration and invasion of HCT-116 cells. knockdown inhibits viability, migration, invasion, and metastasis and the metabolism of glutamine and glucose in HT-29 cells, as well as the expressions of two key glycolytic enzymes, hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). The luciferase activity of the promoter is increased by overexpression. promoter enrichment is increased by anti-ATF4 antibody immunoprecipitation in -overexpressing colorectal cells, indicating that ATF4 targets SLC1A5 to promote glutamine and glucose metabolism in these cells. In summary, the ATF4/SLC1A5 axis plays a significant role in the progression of colorectal cancer by regulating glutamine metabolism and glycolysis.

摘要

谷氨酰胺分解和糖酵解促进结直肠癌的恶性进展。激活转录因子4（ATF4）在溶质载体家族1成员5（SLC1A5）介导的谷氨酰胺分解和糖酵解中的作用仍有待阐明。检测了结直肠癌组织中SLC1A5和ATF4的表达水平。敲低或过表达以评估其在细胞活力、迁移和侵袭中的作用。敲低以评估其在细胞活力、迁移、侵袭和转移以及谷氨酰胺和葡萄糖代谢中的作用。使用荧光素酶报告基因测定法和染色质免疫沉淀（ChIP）技术确定转录因子ATF4对SLC1A5转录和表达的调节作用。在肿瘤组织中观察到ATF4和SLC1A5表达上调，这与肿瘤、淋巴结和转移（TNM）分期呈正相关。过表达SW480细胞显示细胞活力、迁移和侵袭增加。相反，敲低会降低HCT-116细胞的活力、迁移和侵袭。敲低会抑制HT-29细胞的活力、迁移、侵袭和转移以及谷氨酰胺和葡萄糖代谢，以及两种关键糖酵解酶己糖激酶2（HK2）和丙酮酸激酶M2（PKM2）的表达。过表达会增加SLC1A5启动子的荧光素酶活性。在过表达SLC1A5的结直肠癌细胞中，抗ATF4抗体免疫沉淀会增加SLC1A5启动子富集，表明ATF4靶向SLC1A5以促进这些细胞中的谷氨酰胺和葡萄糖代谢。总之，ATF4/SLC1A5轴通过调节谷氨酰胺代谢和糖酵解在结直肠癌进展中起重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/818aebdf5f6c/ABBS-2024-401-t8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/2fda87392781/ABBS-2024-401-t1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/4bd86f008b3d/ABBS-2024-401-t2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/712addc90794/ABBS-2024-401-t3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/722a57365a59/ABBS-2024-401-t4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/c285477623f5/ABBS-2024-401-t5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/0bccd9dabb08/ABBS-2024-401-t6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/e7b731370604/ABBS-2024-401-t7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/818aebdf5f6c/ABBS-2024-401-t8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/2fda87392781/ABBS-2024-401-t1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/4bd86f008b3d/ABBS-2024-401-t2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/712addc90794/ABBS-2024-401-t3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/722a57365a59/ABBS-2024-401-t4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/c285477623f5/ABBS-2024-401-t5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/0bccd9dabb08/ABBS-2024-401-t6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/e7b731370604/ABBS-2024-401-t7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bbd/12383793/818aebdf5f6c/ABBS-2024-401-t8.jpg

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ATF4 promotes glutaminolysis and glycolysis in colorectal cancer by transcriptionally inducing SLC1A5.

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引用本文的文献

[1]
Glucose Metabolic Reprogramming in Colorectal Cancer: From Mechanisms to Targeted Therapy Approaches.

Cancer Med. 2025-9

[2]
Identification of Key Glycolysis-Related Genes in Osteoarthritis and Their Correlation with Immune Infiltration Using Bioinformatics Analysis and Machine Learning.

Open Access Rheumatol. 2025-8-16

本文引用的文献

[1]
The Interaction between Collagen 1 and High Mannose Type CD133 Up-Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells.

Adv Sci (Weinh). 2024-1

[2]
Tumor-associated microbiota in colorectal cancer with vascular tumor thrombus and neural invasion and association with clinical prognosis.

Acta Biochim Biophys Sin (Shanghai). 2024-3-25

[3]
Metabolic signatures and potential biomarkers for the diagnosis and treatment of colon cancer cachexia.

Acta Biochim Biophys Sin (Shanghai). 2023-12-25

[4]
ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis.

Clin Immunol. 2023-9

[5]
Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis.

ESC Heart Fail. 2023-8

[6]
A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response.

Front Mol Neurosci. 2023-2-7

[7]
Overview of Cancer Metabolism and Signaling Transduction.

Int J Mol Sci. 2022-12-20

[8]
Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways.

Cells. 2022-7-7

[9]
Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.

Cell Death Dis. 2022-7-21

[10]
KRAS inhibition in colorectal cancer.

Lancet Oncol. 2022-1

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