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Resistance to bortezomib in breast cancer cells that downregulate Bim through FOXA1 O-GlcNAcylation

Yubo Liu1, Xue Wang1, Tong Zhu1

  • 1Department of Biochemistry, School of Life Science & Medicine, Dalian University of Technology, Panjin, China.

Journal of Cellular Physiology
|February 23, 2019
PubMed

Insights

Bortezomib resistance in breast cancer is linked to elevated O-GlcNAc modification, which reduces the stability of FOXA1 and suppresses apoptosis. Combining Bortezomib with an O-GlcNAc inhibitor can overcome this resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Bortezomib (BTZ) is a proteasome inhibitor used in cancer therapy, but its efficacy varies across cancer types, with limited success in breast cancer.
  • The mechanisms underlying Bortezomib resistance in breast cancer are not fully understood, hindering effective treatment strategies.

Purpose of the Study:

  • To elucidate the molecular mechanisms of Bortezomib resistance in breast cancer cells.
  • To investigate the role of O-GlcNAc modification in Bortezomib resistance.
  • To identify potential therapeutic strategies to overcome Bortezomib resistance.

Main Methods:

  • Treatment of breast cancer cell lines (MCF-7, T47D, MDA-MB-231) with Bortezomib.
  • Assessment of cellular O-GlcNAc modification levels.
  • Analysis of pioneer factor FOXA1 protein stability and its interaction with O-GlcNAc.
  • Evaluation of Bim gene expression and its role in apoptosis.
  • Combination therapy using Bortezomib and an O-GlcNAc inhibitor (L01).

Main Results:

  • Bortezomib treatment significantly increased O-GlcNAc modification in resistant breast cancer cells (MCF-7, T47D) but not in sensitive cells (MDA-MB-231).
  • Acquired Bortezomib resistance in MDA-MB-231 cells correlated with increased O-GlcNAcylation.
  • Elevated O-GlcNAc reduced FOXA1 protein stability, leading to transcriptional downregulation of the proapoptotic gene Bim.
  • This Bim deficiency suppressed Bortezomib-induced apoptosis in resistant breast cancer cells.
  • Co-treatment with Bortezomib and the O-GlcNAc inhibitor L01 sensitized resistant cells to Bortezomib.

Conclusions:

  • Elevated O-GlcNAc modification is a key mechanism contributing to Bortezomib resistance in breast cancer.
  • The O-GlcNAc/FOXA1/Bim pathway regulates apoptosis and Bortezomib sensitivity.
  • Combining Bortezomib with O-GlcNAc inhibitors represents a promising therapeutic strategy to overcome Bortezomib resistance in breast cancer.
Keywords:
FOXA1O-GlcNAcapoptosisbortezomibbreast cancer

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