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

Journal of Cellular Physiology
Yubo LiuJianing Zhang

Abstract

Bortezomib (BTZ), a well-established proteasome inhibitor used in the clinical therapy, leads the modulation of several biological alterations and in turn induces apoptosis. Although clinical trials with BTZ have shown promising results for some types of cancers, but not for some others, including those of the breast. The molecular basis of BTZ resistance in breast cancer remains elusive. In the present study, we found that cellular O-GlcNAc modification was dramatically elevated by BTZ treatment in intrinsic resistant MCF-7 and T47D cells, but not in sensitive MDA-MB-231 cells. A progressive increase in O-GlcNAcylation characterized the increased acquired resistance of MDA-MB-231-derived cells. We showed that elevated O-GlcNAc subsequently modified breast cancer related pioneer factor FOXA1 and reduced its protein stability. Further, we demonstrated that FOXA1 attenuation was involved in transcriptional downregulation of proapoptotic Bim and thus suppressed breast cancer cell apoptosis. Finally, the combination of O-GlcNAc inhibitor L01 to BTZ sensitized resistant cells. Our results have revealed a new regulatory mechanism that involves O-GlcNAc elevation mediated Bim deficiency, which plays a key role in the apoptotic dysregu...Continue Reading

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Citations

Jul 31, 2020·Expert Opinion on Drug Delivery·Saeideh AllahyariParvin Zakeri-Milani
Aug 28, 2020·International Journal of Toxicology·Vivek MakwanaSantosh Rudrawar
Nov 8, 2020·Cell Stress & Chaperones·Yang LiuShi-Ze Li
Apr 24, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Bing GaoJianping Guo
Mar 22, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Vivek MakwanaShailendra Anoopkumar-Dukie

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