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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

Abstract

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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Acknowledgements

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 (www.edanzediting.com/ac) 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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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Nobuyuki Tanaka.

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DOI

https://doi.org/10.1038/s41388-018-0533-4