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IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells

Oncogene (2018) | Download Citation


Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O-GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs.

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We thank Y. Abe. Y. Nakajima, A. Tanimura, and I. Uehara for discussion, and Y. Asano, M. Kawagoe and T. Takatera for technical support. This work was supported by Grants-in-Aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan (MEXT/JSPS KAKEN Grant Number 17H04554). We thank Edanz Group ( for editing a draft of this manuscript.

Author contributions

M.S. and N.T. designed the study, analyzed the data, and wrote the manuscript. M.S. performed the experiments, and M.S. and N.T. analyzed the data.

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  1. Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Japan

    • Masahiro Shimizu
    •  & Nobuyuki Tanaka


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The authors declare that they have no conflict of interest.

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Correspondence to Nobuyuki Tanaka.

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