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

Oncogene. 2019 Feb;38(9):1520-1533. doi: 10.1038/s41388-018-0533-4. Epub 2018 Oct 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / genetics
  • Acylation / genetics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Glucose Transporter Type 3 / genetics*
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / genetics*
  • Humans
  • Interleukin-8 / genetics*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology


  • CXCL8 protein, human
  • Glucose Transporter Type 3
  • Interleukin-8
  • SLC2A3 protein, human
  • GFPT1 protein, human
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
  • Acetylglucosamine