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氨基葡萄糖通过引发细胞凋亡、自噬和抗瓦伯格效应来抑制肝癌细胞的增殖。

Glucosamine Inhibits the Proliferation of Hepatocellular Carcinoma Cells by Eliciting Apoptosis, Autophagy, and the Anti-Warburg Effect.

作者信息

Samizu Misako, Iida Kaoruko

机构信息

Department of Food and Nutritional Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 1128610, Japan.

Division of Nutritional Science, Institute of Human Life Science, Ochanomizu University, Tokyo 1128610, Japan.

出版信息

Scientifica (Cairo). 2025 Jan 8;2025:5685884. doi: 10.1155/sci5/5685884. eCollection 2025.

DOI:10.1155/sci5/5685884
PMID:39816727
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11735062/
Abstract

Although glucosamine (GlcN) exhibits antitumor effects, its mechanism of action remains controversial. Additionally, its impact on hepatocellular carcinoma (HCC) is not well understood. This study aimed to investigate the antitumor effects of GlcN and its underlying mechanism in a mouse HCC cell line, Hepa1-6. GlcN treatment significantly inhibited Hepa1-6 cell proliferation. Gene expression analysis revealed that GlcN upregulated and while downregulating , indicating the involvement of endoplasmic reticulum (ER) stress-induced apoptosis in the antiproliferative effects of GlcN. GlcN also increased the expression of and , known tumor suppressors in various cancers. Furthermore, GlcN treatment elevated the levels of LC3II (an autophagy marker) and AMP-activated protein kinase activity, suggesting intracellular energy shortage. Indeed, GlcN treatment significantly suppressed glycolytic flux, lactate, and ATP production. Supplementing GlcN treatment with a high glucose concentration (20 mM) significantly attenuated its effect. We postulate that GlcN inhibits Hepa1-6 cell growth by inducing ER stress-induced apoptosis and autophagy and by inhibiting aerobic glycolysis (the Warburg effect), a key hallmark of cancer metabolism. Given that glucose transporter 2 (GLUT2), which is abundantly expressed in hepatocytes, has a high affinity for GlcN, these effects may result from GlcN competing with glucose for hepatocyte uptake by GLUT2. Our novel findings have potential implications for HCC treatment.

摘要

尽管氨基葡萄糖（GlcN）具有抗肿瘤作用，但其作用机制仍存在争议。此外，其对肝细胞癌（HCC）的影响尚不完全清楚。本研究旨在探讨GlcN在小鼠肝癌细胞系Hepa1-6中的抗肿瘤作用及其潜在机制。GlcN处理显著抑制Hepa1-6细胞增殖。基因表达分析显示，GlcN上调 和 ，同时下调 ，表明内质网（ER）应激诱导的细胞凋亡参与了GlcN的抗增殖作用。GlcN还增加了 和 的表达，这两种基因在多种癌症中都是已知的肿瘤抑制因子。此外，GlcN处理提高了LC3II（一种自噬标志物）的水平和AMP激活的蛋白激酶活性，提示细胞内能量短缺。事实上，GlcN处理显著抑制了糖酵解通量、乳酸和ATP的产生。用高葡萄糖浓度（20 mM）补充GlcN处理可显著减弱其作用效果。我们推测，GlcN通过诱导ER应激诱导的细胞凋亡和自噬以及抑制有氧糖酵解（瓦伯格效应）来抑制Hepa1-6细胞生长；有氧糖酵解是癌症代谢的一个关键特征。鉴于在肝细胞中大量表达且对GlcN具有高亲和力葡萄糖转运蛋白2（GLUT2），这些作用可能是由于GlcN与葡萄糖竞争通过GLUT2被肝细胞摄取所致。我们的新发现对肝癌治疗具有潜在意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/21c5ca77843a/SCIENTIFICA2025-5685884.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/eff7aab6549a/SCIENTIFICA2025-5685884.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/ab06bf8fb6da/SCIENTIFICA2025-5685884.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/0c5bdb83156d/SCIENTIFICA2025-5685884.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/faa0764e4055/SCIENTIFICA2025-5685884.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/882804d99cd0/SCIENTIFICA2025-5685884.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/21c5ca77843a/SCIENTIFICA2025-5685884.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/eff7aab6549a/SCIENTIFICA2025-5685884.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/ab06bf8fb6da/SCIENTIFICA2025-5685884.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/0c5bdb83156d/SCIENTIFICA2025-5685884.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/faa0764e4055/SCIENTIFICA2025-5685884.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/882804d99cd0/SCIENTIFICA2025-5685884.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a753/11735062/21c5ca77843a/SCIENTIFICA2025-5685884.006.jpg

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[1]
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[2]
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[3]
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[4]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
Glucose transporter 2‑transported glucosamine inhibits glycolysis in cancer cell lines through competition with glucose for hexokinase II.

Oncol Rep. 2025-6

本文引用的文献

[1]
Regular Glucosamine Use May Have Different Roles in the Risk of Site-Specific Cancers: Findings from a Large Prospective Cohort.

Cancer Epidemiol Biomarkers Prev. 2023-4-3

[2]
Association between glucosamine use and cancer mortality: A large prospective cohort study.

Front Nutr. 2022-11-2

[3]
Molecularly Defined Subsets of Ewing Sarcoma Tumors Differ in Their Responses to IGF1R and WEE1 Inhibition.

Clin Cancer Res. 2023-1-17

[4]
Tumor glycolysis, an essential sweet tooth of tumor cells.

Semin Cancer Biol. 2022-11

[5]
Relationship between glucosamine use and the risk of lung cancer: data from a nationwide prospective cohort study.

Eur Respir J. 2022-3-10

[6]
GLUT1 biological function and inhibition: research advances.

Future Med Chem. 2021-7

[7]
Cytoplasmic vacuolation with endoplasmic reticulum stress directs sorafenib induced non-apoptotic cell death in hepatic stellate cells.

Sci Rep. 2021-2-4

[8]
Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect.

Cancer Manag Res. 2020-7-17

[9]
Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma.

Cell Commun Signal. 2020-6-23

[10]
FOXO transcription factor family in cancer and metastasis.

Cancer Metastasis Rev. 2020-9

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