Open AccessInhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells
Author(s) -
Peng Li,
Sarah Diab,
Mingfeng Yu,
Julian Adams,
Saiful Islam,
Sunita K. C. Basnet,
Hugo Albrecht,
Robert W. Milne,
Shudong Wang
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.10796
Subject(s) - cytarabine , myeloid leukemia , small hairpin rna , gene knockdown , apoptosis , medicine , cancer research , leukemia , myeloid , rna interference , p38 mitogen activated protein kinases , pharmacology , immunology , mapk/erk pathway , biology , phosphorylation , rna , microbiology and biotechnology , biochemistry , gene
Cytarabine (Ara-C) is a first line clinical therapeutic agent for treatment of acute myeloid leukemia (AML). However, this therapy is limited due to high rate of resistance and relapse. Recent research has revealed that the poor prognosis and resistance to Ara-C in AML were associated with its abnormally activated MAPK pathways. In this study, we showed a strong synergistic effect of Ara-C with either our Mnk inhibitor (MNKI-8e) or short hairpin RNA (shRNA) mediated knockdown of Mnks in MV4-11 AML cells. We investigated the underlying mechanisms for this synergism. We showed that both MNKI-8e and Mnk shRNAs enhanced the ability of Ara-C to induce apoptosis. We found that Ara-C increased the phosphorylation of Erk1/2, p38 and eIF4E, which correlated with an enhanced level of anti-apoptotic Mcl-1 protein. Inhibition of Mnk activity suppressed the Ara-C-induced MAPK activity, and thus enhanced apoptosis in MV4-11 cells. Taken together, our study suggests that MAPK-Mnk-eIF4E pathway plays a critical role in Ara-C-treated MV4-11 cells and targeting Mnk may be a promising therapeutic strategy for sensitizing leukemic cells to Ara-C therapy.