A groundbreaking study uncovers a potential target for therapeutic intervention in cholangiocarcinoma (CCA), a highly aggressive form of liver cancer. Researchers have identified elevated expression of the facilitative glucose transporter 5 (GLUT5) in human CCA samples, shedding light on its crucial role in tumor proliferation and survival.
The study, conducted by a team of scientists from Japan and Khon Kaen University, Thailand, utilized RNA sequencing data from human tissues and cell lines to compare GLUT5 expression levels. The results demonstrated a significant increase in GLUT5 expression in CCA cells when compared to normal liver tissues or a cholangiocyte cell line.
Moreover, the researchers observed that cells with high levels of GLUT5 exhibited enhanced rates of cell proliferation and adenosine triphosphate (ATP) production, particularly when fructose was present in the growth medium. Conversely, silencing GLUT5 attenuated cell proliferation, ATP production, cell migration/invasion, and improved the balance of epithelial–mesenchymal transition (EMT), a critical process in cancer progression.
In a mouse xenograft model, the consumption of fructose was found to accelerate tumor growth, providing further evidence of the tumor-promoting effect of GLUT5. Remarkably, when GLUT5 expression was suppressed, tumor growth was significantly inhibited, highlighting the therapeutic potential of targeting GLUT5 in CCA treatment.
Furthermore, the study shed light on the metabolic pathways associated with fructose metabolism and the Warburg effect, a characteristic alteration in cellular metabolism observed in cancer cells. The expression levels of key downstream genes involved in fructolysis, including ketohexokinase (KHK), aldolase B (ALDOB), lactate dehydrogenase A (LDHA), monocarboxylate transporter 4 (MCT4), and hypoxia-inducible factor 1 alpha (HIF1A), were found to be modulated in a GLUT5 expression-dependent manner.
These findings provide important insights into the metabolic regulation of CCA and identify GLUT5 as a potential therapeutic target. By understanding the role of GLUT5 in promoting tumor growth and survival, we can explore novel strategies to disrupt its function and develop more effective treatments for cholangiocarcinoma.
The discovery of GLUT5’s involvement in CCA progression opens up new avenues for drug development and personalized treatment approaches. Further research will be necessary to explore the therapeutic potential of targeting GLUT5 and its downstream metabolic pathways in clinical settings.
Funding
This work was supported by JSPS KAKENHI, Japan [No. JP16H05255, JP19H03884 (MM), JP17H04654 (NM)] and scholarship support from the Japanese Government (MEXT) provided to the author (NS).
Original Paper
Title of original paper: Targeting fructose metabolism by glucose transporter 5 regulation in human cholangiocarcinoma
Journal: Genes & Diseases
DOI: 10.1016/j.gendis.2021.09.002.
Correspondence
Mariko Murata