Journal
ACTA PHARMACOLOGICA SINICA
Volume 39, Issue 12, Pages 1894-1901Publisher
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/s41401-018-0161-0
Keywords
T-ALL; mTOR; MNK1; eIF4E; drug-resistance; everolimus; CGP57380
Funding
- Science Technology Department of Zhejiang Province [2016C33137, 2018C03016-1]
- National Natural Science Foundation of China [81670178]
- National Key Research and Development Program of China [2016YFC090150X]
- Research Project for Practice Development of National TCM Clinical Research Bases [JDZX2015113]
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Although the treatment of adult T-cell acute lymphoblastic leukemia (T-ALL) has been significantly improved, the heterogeneous genetic landscape of the disease often causes relapse. Aberrant activation of mammalian target of rapamycin (mTOR) pathway in T-ALL is responsible for treatment failure and relapse, suggesting that mTOR inhibition may represents a new therapeutic strategy. In this study, we investigated whether the mTOR complex 1 (mTORC1) inhibitor everolimus could be used as a therapeutic agent against human T-ALL. We showed that rapamycin and its analog RAD001 (everolimus) exerted only mild inhibition on the viability of Jurkat, CEM and Molt-4 cell lines (for everolimus the maximum inhibition was <40% at 100 nM), but greatly enhanced the phosphorylation of eIF4E, a downstream substrate of MAPK-interacting kinase (MNK) that was involved in promoting cell survival. Furthermore, we demonstrated in Jurkat cells that mTOR inhibitor-induced eIF4E phosphorylation was independent of insulin-like growth factor-1/insulin-like growth factor-1 receptor axis, but was secondary to mTOR inhibition. Then we examined the antileukemia effects of CGP57380, a MNK1 inhibitor, and we found that CGP57380 (4-16 mu M) dose-dependently suppressed the expression of both phosphor-MNK1 and phosphor-eIF4E, thereby inhibiting downstream targets such as c-Myc and survivin in T-ALL cells. Importantly, CGP57380 produced a synergistic growth inhibitory effect with everolimus in T-ALL cells, and treatment with this targeted therapy overcame everolimus-induced eIF4E phosphorylation. In conclusion, our results suggest that dual-targeting of mTOR and MNK1/eIF4E signaling pathways may represent a novel therapeutic strategy for the treatment of human T-ALL.
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