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Cytosolic galectin-7 impairs p53 functions and induces chemoresistance in breast cancer cells

Grosset, Andrée-Anne; Labrie, Marilyne; Gagné, Donald; Vladoiu, Maria Claudia; Gaboury, Louis; Doucet, Nicolas; St-Pierre, Yves (2014). Cytosolic galectin-7 impairs p53 functions and induces chemoresistance in breast cancer cells BMC Cancer , vol. 14 . p. 801. DOI: 10.1186/1471-2407-14-801.

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Résumé

BACKGROUND: Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 (gal-7) was recently shown to be specifically expressed in basal-like but not in luminal subtypes of human breast cancer. METHODS: We generated a mutant form of gal-7 (R74S). Arginine 74 is the structural equivalent of arginine 186 found in human galectin-3. Mutation R186S was previously shown to abolish the biological function of galectin-3. RESULTS: Mutation of arginine 74 induced only limited and local changes to the gal-7 fold. Recombinant forms of R74S and wtgal-7 were also equally effective at forming dimers in solution. Analysis of the thermodynamic parameters by isothermal titration calorimetry (ITC) indicated, however, that binding of lactose to gal-7 was inhibited by the R74S mutation. Using confocal microscopy and electron microscopy, we confirmed the expression of gal-7 in the cytosolic and nuclear compartments of breast cancer cells and the ability of gal-7 to translocate to mitochondria. The mutation at position 74, however, greatly reduced the expression of gal-7 in the nuclear and mitochondrial compartments. Interestingly, cells expressing mutated gal-7 were equally if not even more resistant to drug-induced apoptosis when compared to cells expressing wtgal-7. We also found that both wtgal-7 and R74S inhibited dox-induced PARP-1 cleavage and p53 protein expression. The inhibition of p53 correlated with a decrease in p21 protein expression and CDKN1A mRNA. Furthermore, analysis of nuclear and cytoplasmic fractions showed that both wild type and R74S mutant gal-7 inhibited p53 nuclear translocation, possibly by increasing degradation of cytosolic p53. CONCLUSIONS: These findings pose a challenge to the paradigm that has guided the design of galectin-specific inhibitors for the treatment of cancer. This study suggests that targeting CRD-independent cytosolic gal-7 in breast cancer cells may be a valuable strategy for the treatment of this disease. Our study will thus complement efforts towards improving selectivity of targeted anticancer agents.

Type de document:
Mots-clés libres: Galectin-7 Localization Apoptosis p53 Breast cancer
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 09 mars 2016 15:28
Dernière modification: 11 janv. 2017 20:49
URI: http://espace.inrs.ca/id/eprint/3048

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