O-GlcNAc elevation through activation of the hexosamine biosynthetic pathway enhances cancer cell chemoresistance

Cell Death Dis. 2018 May 1;9(5):485. doi: 10.1038/s41419-018-0522-0.


Chemoresistance has become a major obstacle to the success of cancer therapy, but the mechanisms underlying chemoresistance are not yet fully understood. O-GlcNAcylation is a post-translational modification that is regulated by the hexosamine biosynthetic pathway (HBP) and has an important role in a wide range of cellular functions. Here we assessed the role of O-GlcNAcylation in chemoresistance and investigated the underlying cellular mechanisms. The results showed that the HBP has an important role in cancer cell chemoresistance by regulating O-GlcNAcylation. An increase in the levels of O-GlcNAcylation indicates an increased resistance of cancer cells to chemotherapy. Acute treatment with doxorubicin (DOX) or camptothecin (CPT) induced O-GlcNAcylation through HBP activation. In fact, the chemotherapy agents activated the AKT/X-box-binding protein 1 (XBP1) axis and then induced the HBP. Furthermore, the observed elevation of cellular O-GlcNAcylation led to activation of survival signalling pathways and chemoresistance in cancer cells. Finally, suppression of O-GlcNAcylation reduced the resistance of both established and primary cancer cells to chemotherapy. These results provide significant novel insights regarding the important role of the HBP and O-GlcNAcylation in regulating cancer chemoresistance. Thus, O-GlcNAc inhibition might offer a new strategy for improving the efficacy of chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Camptothecin / pharmacology*
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Energy Metabolism*
  • Glycosylation
  • HL-60 Cells
  • HeLa Cells
  • Hexosamines / biosynthesis*
  • Humans
  • MCF-7 Cells
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Protein Processing, Post-Translational*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism


  • Antineoplastic Agents
  • Hexosamines
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Doxorubicin
  • Proto-Oncogene Proteins c-akt
  • Camptothecin