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O-GlcNAcylation-Inducing Treatments Inhibit Estrogen Receptor α Expression and Confer Resistance to 4-OH-Tamoxifen in Human Breast Cancer-Derived MCF-7 Cells

Author

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  • Shahzina Kanwal
  • Yann Fardini
  • Patrick Pagesy
  • Thierry N’Tumba-Byn
  • Cécile Pierre-Eugène
  • Elodie Masson
  • Cornelia Hampe
  • Tarik Issad

Abstract

O-GlcNAcylation (addition of N-acetyl-glucosamine on serine or threonine residues) is a post-translational modification that regulates stability, activity or localization of cytosolic and nuclear proteins. O-linked N-acetylgluocosmaine transferase (OGT) uses UDP-GlcNAc, produced in the hexosamine biosynthetic pathway to O-GlcNacylate proteins. Removal of O-GlcNAc from proteins is catalyzed by the β-N-Acetylglucosaminidase (OGA). Recent evidences suggest that O-GlcNAcylation may affect the growth of cancer cells. However, the consequences of O-GlcNAcylation on anti-cancer therapy have not been evaluated. In this work, we studied the effects of O-GlcNAcylation on tamoxifen-induced cell death in the breast cancer-derived MCF-7 cells. Treatments that increase O-GlcNAcylation (PUGNAc and/or glucosoamine) protected MCF-7 cells from death induced by tamoxifen. In contrast, inhibition of OGT expression by siRNA potentiated the effect of tamoxifen on cell death. Since the PI-3 kinase/Akt pathway is a major regulator of cell survival, we used BRET to evaluate the effect of PUGNAc+glucosamine on PIP3 production. We observed that these treatments stimulated PIP3 production in MCF-7 cells. This effect was associated with an increase in Akt phosphorylation. However, the PI-3 kinase inhibitor LY294002, which abolished the effect of PUGNAc+glucosamine on Akt phosphorylation, did not impair the protective effects of PUGNAc+glucosamine against tamoxifen-induced cell death. These results suggest that the protective effects of O-GlcNAcylation are independent of the PI-3 kinase/Akt pathway. As tamoxifen sensitivity depends on the estrogen receptor (ERα) expression level, we evaluated the effect of PUGNAc+glucosamine on the expression of this receptor. We observed that O-GlcNAcylation-inducing treatment significantly reduced the expression of ERα mRNA and protein, suggesting a potential mechanism for the decreased tamoxifen sensitivity induced by these treatments. Therefore, our results suggest that inhibition of O-GlcNAcylation may constitute an interesting approach to improve the sensitivity of breast cancer to anti-estrogen therapy.

Suggested Citation

  • Shahzina Kanwal & Yann Fardini & Patrick Pagesy & Thierry N’Tumba-Byn & Cécile Pierre-Eugène & Elodie Masson & Cornelia Hampe & Tarik Issad, 2013. "O-GlcNAcylation-Inducing Treatments Inhibit Estrogen Receptor α Expression and Confer Resistance to 4-OH-Tamoxifen in Human Breast Cancer-Derived MCF-7 Cells," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-1, July.
    • Handle: RePEc:plo:pone00:0069150
    DOI: 10.1371/journal.pone.0069150
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    1. Xiaoyong Yang & Pat P. Ongusaha & Philip D. Miles & Joyce C. Havstad & Fengxue Zhang & W. Venus So & Jeffrey E. Kudlow & Robert H. Michell & Jerrold M. Olefsky & Seth J. Field & Ronald M. Evans, 2008. "Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance," Nature, Nature, vol. 451(7181), pages 964-969, February.
    2. Gerald W. Hart & Michael P. Housley & Chad Slawson, 2007. "Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins," Nature, Nature, vol. 446(7139), pages 1017-1022, April.
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