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.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of pediatric and 25% of adult cases of ALL
Using an unbiased proteomic approach to identify proteins possibly relevant to the oncogenic properties of Cn in T-ALL, we identified novel and known PPP3CAinteracting proteins implicated in numerous cellular signaling pathways, including eIF2 signaling, cell cycle control, mammalian target of Rapamycin (mTOR) signaling and 14-3-3 mediated signaling
Several proteins implicated in leukemia pathobiology emerged amongst the novel PPP3CA interactors such as Rb, NPM1, BCL11b, GSK3β and KDM1
Summary
T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of pediatric and 25% of adult cases of ALL. Cn has the ability to dephosphorylate a broad range of proteins, including Nuclear Factor of Activated T cells (NFAT) proteins. Critically www.impactjournals.com/oncotarget involved in many aspects of normal T cell survival, proliferation and activation, the direct implication of Cn and/or its downstream NFAT targets in lymphomagenesis and cancer in general has only recently been reported [6, 7]. It is possible that NFAT factors are not the only targets of Cn in leukemogenesis, as Cn can dephosphorylate other factors possibly relevant to its oncogenic properties. With this perspective in mind, we used tandem affinity chromatography, followed by mass spectrometry (MS) to purify novel Cn-interacting partners in human T-ALL cells. We explored the potential therapeutic importance of the functional interaction between the top signaling pathways enriched in our PPP3CA complex and the canonical Cn-NFAT signaling pathway
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