Int J Biol Sci 2022; 18(9):3668-3675. doi:10.7150/ijbs.68990 This issue

Research Paper

IL-6/STAT3 Axis Activates Glut5 to Regulate Fructose Metabolism and Tumorigenesis

Xiaoke Huang1,#, Jing Fang2,#, Weiqi Lai1, Yu Hu1, Liang Li1, Yuanyou Zhong1, Shiwei Yang1, Dan He3, Rui Liu4,✉, Qingfeng Tang1,#,✉

1. Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
2. Department of Nephrology, The sixth people's hospital of Chengdu, Chengdu, 610051, China
3. The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, P. R. China
4. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P. R. China
#These authors contribute equally to this work.

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Citation:
Huang X, Fang J, Lai W, Hu Y, Li L, Zhong Y, Yang S, He D, Liu R, Tang Q. IL-6/STAT3 Axis Activates Glut5 to Regulate Fructose Metabolism and Tumorigenesis. Int J Biol Sci 2022; 18(9):3668-3675. doi:10.7150/ijbs.68990. Available from https://www.ijbs.com/v18p3668.htm

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Abstract

Graphic abstract

Cancer cells frequently use fructose as an alternative energy and carbon source, to fuel glycolysis and support the synthesis of various biomacromolecules. Glut5 is the only fructose-specific transporter, which lacks the ability to transport other carbohydrates such as glucose and galactose. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. Nevertheless, how inflammatory factors coordinate with fructose metabolism to facilitate tumor growth remains largely elusive. Here we show that treatment with IL-6 activates fructose uptake and fructolysis in oral squamous cell carcinoma (OSCC) cells and prostate cancer cells. Mechanistic study shows that transcription factor STAT3 associates with Glut5 promoter region and enhances Glut5 transcription in response to IL-6 treatment. Knockdown of Glut5 abolished IL-6-induced fructose uptake and utilization of fructose, and compromises IL-6-elicited tumor cell proliferation. Further, positive correlation between Glut5 and IL-6 expression is observed in multiple cancers. Our findings demonstrate a regulatory cascade underlying the crosstalk between inflammation and fructose metabolism in cancer cells, and highlights Glut5 as a novel oncogenic factor.

Keywords: IL-6, STAT3, Glut5, fructose metabolism, tumorigenesis