A Pyrazolo[3,4-d]pyrimidine compound inhibits Fyn phosphorylation and induces apoptosis in natural killer cell leukemia

Ilaria Laurenzana, Antonella Caivano, Stefania Trino, Luciana De Luca, Francesco La Rocca, Vittorio Simeon, Cristina Tintori, Francesca D'Alessio, Antonella Teramo, Renato Zambello, Antonio Traficante, Maddalena Maietti, Gianpietro Semenzato, Silvia Schenone, Maurizio Botta, Pellegrino Musto, Luigi Del Vecchio

Research output: Contribution to journalArticle

Abstract

Natural killer (NK) cell neoplasms are characterized by clonal proliferation of cytotoxic NK cells. Since there is no standard treatment to date, new therapeutic options are needed, especially for NK aggressive tumors. Fyn tyrosine kinase has a key role in different biological processes, such as cell growth and differentiation, being also involved in the pathogenesis of hematologic malignancies. Our previous studies led us to identify 4c pyrazolo[3,4-d]pyrimidine compound capable of inhibiting Fyn activation and inducing apoptosis in different cancer cell lines. Here we investigated the presence of Fyn and the effect of its inhibitor in NK malignant cells. Firstly, we showed Fyn over-expression in NK leukemic cells compared to peripheral blood mononuclear cells from healthy donors. Subsequently, we demonstrated that 4c treatment reduced cell viability, induced caspase 3-mediate apoptosis and cell cycle arrest in NK cells. Moreover, by inhibiting Fyn phosphorylation, 4c compound reduced Akt and P70 S6 kinase activation and changed the expression of genes involved in cell death and survival in NK cells. Our study demonstrated that Fyn is involved in the pathogenesis of NK leukemia and that it could represent a potential target for this neoplasm. Moreover, we proved that Fyn inhibitor pyrazolo[3,4-d]pyrimidine compound, could be a started point to develop new therapeutic agents.

Original languageEnglish
Pages (from-to)65171-65184
Number of pages14
JournalOncotarget
Volume7
Issue number40
DOIs
Publication statusPublished - 2016

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Keywords

  • Fyn tyrosine kinase
  • Kinase inhibitor
  • Natural killer large granular lymphocyte leukemia
  • NK cells

ASJC Scopus subject areas

  • Oncology

Cite this

Laurenzana, I., Caivano, A., Trino, S., De Luca, L., La Rocca, F., Simeon, V., Tintori, C., D'Alessio, F., Teramo, A., Zambello, R., Traficante, A., Maietti, M., Semenzato, G., Schenone, S., Botta, M., Musto, P., & Del Vecchio, L. (2016). A Pyrazolo[3,4-d]pyrimidine compound inhibits Fyn phosphorylation and induces apoptosis in natural killer cell leukemia. Oncotarget, 7(40), 65171-65184. https://doi.org/10.18632/oncotarget.11496