ArticleOncotarget2016
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.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Article
- Peroxiredoxins wear many hats: Factors that fashion their peroxide sensing personalities.Redox biology · 2021Review
- Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target.NPJ precision oncology · 2021Article
- BCL11B Regulates Arterial Stiffness and Related Target Organ Damage.Circulation research · 2021Article
- NFAT transcription factors are essential and redundant actors for leukemia initiating potential in T-cell acute lymphoblastic leukemia.PloS one · 2021Article
- Identifying New Substrates and Functions for an Old Enzyme: Calcineurin.Cold Spring Harbor perspectives in biology · 2020Review
- C1222C Deletion in Exon 8 ofFrontiers in oncology · 2020Article
- Quantitative Proteomic Analysis and Evaluation of the Potential Prognostic Biomarkers in Cholangiocarcinoma.Journal of Cancer · 2019Article
- Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update.International journal of molecular sciences · 2018Review
- Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2017Review
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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