3.8 Article

Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma

Journal

GENES & DISEASES
Volume 9, Issue 6, Pages 1727-1741

Publisher

ELSEVIER
DOI: 10.1016/j.gendis.2021.09.002

Keywords

Cholangiocarcinoma; Glucose transporter; Metabolic regulation; Warburg effect

Funding

  1. JSPS KAKENHI, Japan
  2. Japanese Government (MEXT)
  3. [JP16H05255]
  4. [JP19H03884]
  5. [JP17H04654]

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Elevated expression of GLUT5 in human cholangiocarcinoma is associated with poor prognosis and contributes to tumor proliferation and survival through modulation of cellular metabolism.
Alterations in cellular metabolism may contribute to tumor proliferation and sur-vival. Upregulation of the facilitative glucose transporter (GLUT) plays a key role in promoting cancer. GLUT5 mediates modulation of fructose utilization, and its overexpression has been associated with poor prognosis in several cancers. However, its metabolic regulation remains poorly understood. Here, we demonstrated elevated GLUT5 expression in human cholangiocar-cinoma (CCA), using RNA sequencing data from samples of human tissues and cell lines, as compared to normal liver tissues or a cholangiocyte cell line. Cells exhibiting high-expression of GLUT5 showed increased rates of cell proliferation and ATP production, partic-ularly in a fructose-supplemented medium. In contrast, GLUT5 silencing attenuated cell pro-liferation, ATP production, cell migration/invasion, and improved epithelial-mesenchymal transition (EMT) balance. Correspondingly, fructose consumption increased tumor growth in a nude mouse xenograft model, and GLUT5 silencing suppressed growth, supporting the tumor-inhibitory effect of GLUT5 downregulation. Furthermore, in the metabolic pathways of fructolysis-Warburg effect, the expression levels of relative downstream genes, including ketohexokinase (KHK), aldolase B (ALDOB), lactate dehydrogenase A (LDHA), and monocarbox-ylate transporter 4 (MCT4), as well as hypoxia-inducible factor 1 alpha (HIF1A), were altered in a GLUT5 expression-dependent manner. Taken together, these findings indicate that GLUT5 could be a potential target for CCA therapeutic approach via metabolic regulation.Copyright 2021, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

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