Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma

Nattawan Suwannakul; Napat Armartmuntree; Raynoo Thanan; Kaoru Midorikawa; Tetsuo Kon; Shinji Oikawa; Hatasu Kobayashi; Ning Ma; Shosuke Kawanishi; Mariko Murata

doi:10.1016/j.gendis.2021.09.002

Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma

Genes Dis. 2021 Oct 2;9(6):1727-1741. doi: 10.1016/j.gendis.2021.09.002. eCollection 2022 Nov.

Authors

Affiliations

¹ Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
² Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
³ Laboratory of Functional Genomics, Graduate School of Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama, Shiga 526-0829, Japan.
⁴ Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan.
⁵ Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan.

Abstract

Alterations in cellular metabolism may contribute to tumor proliferation and survival. 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 cholangiocarcinoma (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, particularly in a fructose-supplemented medium. In contrast, GLUT5 silencing attenuated cell proliferation, 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 monocarboxylate 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.

Keywords: Cholangiocarcinoma; Fructose; Glucose transporter 5; Metabolic regulation; Warburg effect.