Oncotarget

Research Papers:

Calcineurin complex isolated from T-cell acute lymphoblastic leukemia (T-ALL) cells identifies new signaling pathways including mTOR/AKT/S6K whose inhibition synergize with calcineurin inhibition to promote T-ALL cell death

Valeria Tosello _, Valentina Saccomani, Jiyang Yu, Fulvio Bordin, Alberto Amadori and Erich Piovan

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Oncotarget. 2016; 7:45715-45729. https://doi.org/10.18632/oncotarget.9933

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Abstract

Valeria Tosello1, Valentina Saccomani2, Jiyang Yu3,4,5, Fulvio Bordin2, Alberto Amadori1,2, Erich Piovan1,2

1UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, 35128, Italy

2Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Sezione di Oncologia, Universita’ di Padova, Padova, 35128, Italy

3Department of Biomedical Informatics, Columbia University, New York, NY, 10032, USA

4Department of Systems Biology, Columbia University, New York, NY, 10032, USA

5Present address: Department of Precision Medicine, Oncology Research Unit, Pfizer Inc., Pearl River, NY, 10965, USA

Correspondence to:

Erich Piovan, email: erich.piovan@unipd.it

Keywords: calcineurin, T-cell acute lymphoblastic leukemia, mTOR signaling, apoptosis, protein complex

Received: October 06, 2015    Accepted: May 28, 2016    Published: June 10, 2016

ABSTRACT

Calcineurin (Cn) is a calcium activated protein phosphatase involved in many aspects of normal T cell physiology, however the role of Cn and/or its downstream targets in leukemogenesis are still ill-defined. In order to identify putative downstream targets/effectors involved in the pro-oncogenic activity of Cn in T-cell acute lymphoblastic leukemia (T-ALL) we used tandem affinity chromatography, followed by mass spectrometry to purify novel Cn-interacting partners. We found the Cn-interacting proteins to be part of numerous cellular signaling pathways including eIF2 signaling and mTOR signaling. Coherently, modulation of Cn activity in T-ALL cells determined alterations in the phosphorylation status of key molecules implicated in protein translation such as eIF-2α and ribosomal protein S6. Joint targeting of PI3K-mTOR, eIF-2α and 14-3-3 signaling pathways with Cn unveiled novel synergistic pro-apoptotic drug combinations. Further analysis disclosed that the synergistic interaction between PI3K-mTOR and Cn inhibitors was prevalently due to AKT inhibition. Finally, we showed that the synergistic pro-apoptotic response determined by jointly targeting AKT and Cn pathways was linked to down-modulation of key anti-apoptotic proteins including Mcl-1, Claspin and XIAP. In conclusion, we identify AKT inhibition as a novel promising drug combination to potentiate the pro-apoptotic effects of Cn inhibitors.


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