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A shift from N-glycolyl- to N-acetyl-sialic acid in the GM3 ganglioside impairs tumor development in mouse lymphocytic leukemia cells

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Abstract

Humans, in contrast to other mammals, do not synthesize N-glycolyl-neuraminic acid (Neu5Gc) due to a deletion in the gene (cmah) encoding the enzyme responsible for this conversion, the cytidine monophospho-N-acetyl-neuraminic acid hydroxylase (CMP-Neu5Ac hydroxylase). The detection of considerable amounts of Neu5Gc-sialoconjugates, in particular gangliosides, in human malignancies makes these antigens attractive targets for immunotherapy, in particular with monoclonal antibodies (mAbs). We have previously described a GM3(Neu5Gc) ganglioside-specific mAb, named 14F7, with the ability to kill tumor cells in a complement-independent manner. Silencing the cmah gene in GM3(Neu5Gc)-expressing L1210 mouse lymphocytic leukemia B cells caused the abrogation of this cytotoxic effect. We now show that cmah-silenced L1210 cells (cmah-kd) express a high level of GM3(Neu5Ac) and have an impaired ability for anchorage-independent cell growth and tumor development in vivo. No evidences of increased immunogenicity of the cmah-kd cell line were found. These results provide new evidences on the role of GM3(Neu5Gc), or Neu5Gc-sialoconjugates in general, in tumor biology. As an important tool in this study, we used the humanized version (here referred to as 7C1 mAb) of a recently described, rationally-designed mutant of 14F7 mAb that is able to bind to both GM3(Neu5Gc) and GM3(Neu5Ac). In contrast to its parental antibody, the humanized 14F7 (14F7hT) mAb, 7C1 mAb was able to kill not only GM3(Neu5Gc)-expressing L1210 wild type cells, but also GM3(Neu5Ac)-expressing cmah-kd cells, which endorses this antibody as a potential agent for cancer immunotherapy.

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Acknowledgments

We thank Dr. Luis Enrique Fernández for his valuable comments on the project. We are also grateful to our fellow researchers Alex Miranda, Darel Martínez, Mayrel Labrada, Nely Rodríguez and Drs. Ana María Hernández and Adriana Carr, as well as technicians Judith Raymond and Katya Sosa for their help. This work was supported by the Center of Molecular Immunology.

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  1. Yuniel Fernández-Marrero

    Present address: University of Bern, 3012, Bern, Switzerland

Authors and Affiliations

  1. Immunobiology Division, Center of Molecular Immunology, P.O. Box 16040, Havana, 11600, Cuba

    Ana Victoria Casadesús, Yuniel Fernández-Marrero, Marilyn Clavell, Tays Hernández & Alejandro López-Requena

  2. Tumor Immunology Division, Center of Molecular Immunology, P.O. Box 16040, Havana, 11600, Cuba

    Ernesto Moreno

  3. Systems Biology Division, Center of Molecular Immunology, P.O. Box 16040, Havana, 11600, Cuba

    José Alberto Gómez

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  1. Ana Victoria Casadesús
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Correspondence to Alejandro López-Requena.

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Ana Victoria Casadesús and Yuniel Fernández-Marrero contributed equally to this work

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Casadesús, A.V., Fernández-Marrero, Y., Clavell, M. et al. A shift from N-glycolyl- to N-acetyl-sialic acid in the GM3 ganglioside impairs tumor development in mouse lymphocytic leukemia cells. Glycoconj J 30, 687–699 (2013). https://doi.org/10.1007/s10719-013-9473-y

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