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.
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.
UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, 35128, Italy.
Valeria
V
Tosello
Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Sezione di Oncologia, Universita' di Padova, Padova, 35128, Italy.
Valentina
V
Saccomani
Department of Biomedical Informatics, Columbia University, New York, NY, 10032, USA.|Department of Systems Biology, Columbia University, New York, NY, 10032, USA.|Present address: Department of Precision Medicine, Oncology Research Unit, Pfizer Inc., Pearl River, NY, 10965, USA.
Jiyang
J
Yu
Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Sezione di Oncologia, Universita' di Padova, Padova, 35128, Italy.
Fulvio
F
Bordin
UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, 35128, Italy.|Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Sezione di Oncologia, Universita' di Padova, Padova, 35128, Italy.
Alberto
A
Amadori
UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, 35128, Italy.|Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Sezione di Oncologia, Universita' di Padova, Padova, 35128, Italy.
Erich
E
Piovan
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050778:NFATC Transcription Factors / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D065095:Calcineurin Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D050778:NFATC Transcription Factors; D016572:Cyclosporine; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; C525673:PPP3CA protein, human
T-cell acute lymphoblastic leukemia; apoptosis; calcineurin; mTOR signaling; protein complex