Effect of O-GlcNAcylation on tamoxifen sensitivity in breast cancer derived MCF-7 cells

par Shahzina Kanwal

Thèse de doctorat en Biologie cellulaire

Sous la direction de Tarik Issad.

Le président du jury était Charbel Massaad.

Le jury était composé de Tarik Issad, Charbel Massaad, Danièle Lacasa, Tony Lefebvre, Etienne Guillot.

Les rapporteurs étaient Danièle Lacasa, Tony Lefebvre.

  • Titre traduit

    Effet de la O-GlcNAcylation sur la sensibilité du tamoxifène dans le cancer du sein dérivé des cellules MCF-7

  • Résumé

    Pas de résumé en français

  • Résumé

    One of the hallmarks of cancer cells is to exhibit increased uptake and consumption of glucose.3-5% of the glucose entering into the cell leads to a minor pathway of the glucose metabolismknown as the hexosamine biosynthetic pathway (HBP). UDP-N-acetylglucosamine is the endproduct of HBP and is used as substrate by OGT (O-GlcNAc transferase) to modify diverserange of nuclear and cytoplasmic proteins with a recently characterized post-translationalmodification called O-GlcNAcylation. It corresponds to the addition of sugar moiety O-linked β-N-acetylglucosamine (O-GlcNAc) on serine or threonine residue of proteins. This process isantagonized by another enzyme called O-GlcNAcase (OGA). Recent studies indicated thepresence of increased O-GlcNAcylation level in several cancer cells. Moreover, inhibition ofOGT has been shown to reduce in vivo and in vitro tumor growth of breast cancer cells.However, the relationship between O-GlcNAcylation and the response to anti-cancer therapy hasnot been studied. Tamoxifen is the oldest and most prescribed selective-estrogen receptormodulator (SERM) for patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen isknown to reduce tumor growth and invasion. Despite its beneficial effects de novo and acquiredresistance are great obstacles in its clinical effectiveness. We found that O-GlcNAc elevation inMCF-7 cells protected them from tamoxifen-induced cell death. Increased O-GlcNAc alsoincreased PI3-K/Akt signaling. However, the protective effect of PUGNAc+glucosamine fromtamoxifen-induced cell death is independent of PI3K/Akt pathway. Increased O-GlcNAcylationalso led to reduced ESR1 promoter activity and decreased expression of ERα at mRNA andprotein levels. The decrease in ERα expression is correlated with a reduced expression of twotamoxifen regulated genes i.e. early growth response 1 and p21 Waf1/Cip1. In conclusion, thisstudy showed for the first time the involvement of O-GlcNAcylation in reducing tamoxifen142sensitivity in MCF-7 cells. Thus, OGT can act as a novel therapeutic target for treatment oftamoxifen resistant cells.

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