Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells

Teo, Theodosia; Yu, Mingfeng; Yang, Yuchao; Gillam, Todd A.; Lam, Frankie; Sykes, Matthew J.; Wang, Shudong

doi:10.1016/j.canlet.2014.12.029

Cited by 39 publications

(38 citation statements)

References 59 publications

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“…Elevated eIF4E levels have been shown to enhance the translational levels of a wide array of malignancy-related mRNAs involved in the regulation of cell senescence, proliferation, and apoptosis, including cyclin D1 and Mcl-1 (Zimmer et al, 2000), whereas the oncogenic functions of eIF4E are closely linked to its phosphorylation by Mnks Diab et al, 2014a). Consistent with previous studies (Zhang et al, 2008;Diab et al, 2014b;Teo et al, 2015), Mnk inhibitors in the current study triggered a cell cycle arrest in both MOLM-13 and MV4-11 cells by disrupting the transition of the G 1 phase to the S phase. Such an effect is likely to be the result of decreased expression of the key cell cycle regulators, including CDK4 and cyclin D3, which further hampered the phosphorylation of Rb at the CDK4-specific Thr826 site (Macdonald and Dick, 2012).…”

Section: Mapk-interacting Kinase Inhibition In Amlsupporting

confidence: 86%

Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia

Teo

Lam

et al. 2015

Mol Pharmacol

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The Ras/Raf/MAPK and PI3K/Akt/mTOR pathways are key signaling cascades involved in the regulation of cell proliferation and survival, and have been implicated in the pathogenesis of several types of cancers, including acute myeloid leukemia (AML). The oncogenic activity of eIF4E driven by the Mnk kinases is a convergent determinant of the two cascades, suggesting that targeting the Mnk/eIF4E axis may provide therapeutic opportunity for the treatment of cancer. Herein, a potent and selective Mnk2 inhibitor (MNKI-85) and a dual-specific Mnk1 and Mnk2 inhibitor (MNKI-19), both derived from a thienopyrimidinyl chemotype, were selected to explore their antileukemic properties. MNKI-19 and MNKI-85 are effective in inhibiting the growth of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation. Further mechanistic studies show that the downstream effects with respect to the selective Mnk1/2 kinase inhibition in AML cells causes G 1 cell cycle arrest followed by induction of apoptosis. MNKI-19 and MNKI-85 demonstrate similar Mnk2 kinase activity and cellular antiproliferative activity but exhibit different time-dependent effects on cell cycle progression and apoptosis. Collectively, this study shows that pharmacologic inhibition of both Mnk1 and Mnk2 can result in a more pronounced cellular response than targeting Mnk2 alone. However, MNKI-85, a first-in-class inhibitor of Mnk2, can be used as a powerful pharmacologic tool in studying the Mnk2/eIF4E-mediated tumorigenic mechanism. In conclusion, this study provides a better understanding of the mechanism underlying the inhibition of AML cell growth by Mnk inhibitors and suggests their potential utility as a therapeutic agent for AML.

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Section: Mapk-interacting Kinase Inhibition In Amlsupporting

confidence: 86%

Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia

Teo

Lam

et al. 2015

Mol Pharmacol

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“…MYLPF is a marker of fast skeletal muscle, and RYR1 functions as a calcium release channel in muscle contraction (Eltit et al., 2010; Wang et al., 2007). AKT2 could enhance myogenic differentiation, and MKNK2 could promote cell proliferation (Heron‐Milhavet, Mamaeva, Rochat, Lamb & Fernandez, 2008; Maimon et al., 2014; Teo et al., 2015). All these effector genes were downregulated during development, implying that the genes and signals identified through WGCNA were important for the differentiation of satellite cells.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of TGFβ2, WNT9a, and FGFR4 signals attenuate satellite cell differentiation during skeletal muscle development

Zhang

et al. 2018

Aging Cell

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SummarySatellite cells play a key role in the aging, generation, and damage repair of skeletal muscle. The molecular mechanism of satellite cells in these processes remains largely unknown. This study systematically investigated for the first time the characteristics of mouse satellite cells at ten different ages. Results indicated that the number and differentiation capacity of satellite cells decreased with age during skeletal muscle development. Transcriptome analysis revealed that 2,907 genes were differentially expressed at six time points at postnatal stage. WGCNA and GO analysis indicated that 1,739 of the 2,907 DEGs were mainly involved in skeletal muscle development processes. Moreover, the results of WGCNA and protein interaction analysis demonstrated that Tgfβ2, Wnt9a, and Fgfr4 were the key genes responsible for the differentiation of satellite cells. Functional analysis showed that TGFβ2 and WNT9a inhibited, whereas FGFR4 promoted the differentiation of satellite cells. Furthermore, each two of them had a regulatory relationship at the protein level. In vivo study also confirmed that TGFβ2 could regulate the regeneration of skeletal muscle, as well as the expression of WNT9a and FGFR4. Therefore, we concluded that the synergistic effects of TGFβ2, WNT9a, and FGFR4 were responsible for attenuating of the differentiation of aging satellite cells during skeletal muscle development. This study provided new insights into the molecular mechanism of satellite cell development. The target genes and signaling pathways investigated in this study would be useful for improving the muscle growth of livestock or treating muscle diseases in clinical settings.

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“…However, in prostate cancer cells, rapamycin and CGP inhibit different spectra of cyclin mRNAs (19). Also, the combination of inhibitors suppressing the mTOR/4E-BP1 and MNK/eIF4E pathways triggers apoptosis in cutaneous lymphomas (105), reduces glioblastoma growth (96), and suppresses proliferation and induces apoptosis in leukemia cells (106), but this does not occur with either inhibitor separately. These results suggest that the MNK/eIF4E and mTOR/ 4E-BP1 pathways affect the translation of different spectra of mRNAs, despite the fact that they both increase eIF4F assembly.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5′-Terminal Cap and Hairpin

Korneeva

Song

Gram

et al. 2016

Journal of Biological Chemistry

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The MAPK-interacting kinases 1 and 2 (MNK1 and MNK2) are activated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) or p38 in response to cellular stress and extracellular stimuli that include growth factors, cytokines, and hormones. Modulation of MNK activity affects translation of mRNAs involved in the cell cycle, cancer progression, and cell survival. However, the mechanism by which MNK selectively affects translation of these mRNAs is not understood. MNK binds eukaryotic translation initiation factor 4G (eIF4G) and phosphorylates the cap-binding protein eIF4E. Using a cell-free translation system from rabbit reticulocytes programmed with mRNAs containing different 5-ends, we show that an MNK inhibitor, CGP57380, affects translation of only those mRNAs that contain both a cap and a hairpin in the 5-UTR. Similarly, a C-terminal fragment of human eIF4G-1, eIF4G(1357-1600), which prevents binding of MNK to intact eIF4G, reduces eIF4E phosphorylation and inhibits translation of only capped and hairpin-containing mRNAs. Analysis of proteins bound to m 7 GTP-Sepharose reveals that both CGP and eIF4G(1357-1600) decrease binding of eIF4E to eIF4G. These data suggest that MNK stimulates translation only of mRNAs containing both a cap and 5-terminal RNA duplex via eIF4E phosphorylation, thereby enhancing the coupled cap-binding and RNA-unwinding activities of eIF4F.The rate of translational initiation in eukaryotic cells depends on both cis-acting features of individual mRNAs, such as the cap, poly(A) tract, and untranslated regions (UTRs), and trans-acting components, such as initiation factors, protein kinases, and microRNAs (1-3). The recruitment of capped mRNAs to 48S initiation complexes involves several discrete steps that include cap recognition by eukaryotic translation initiation factor 4E (eIF4E), 3 mRNA binding by eIF4G, ATP-dependent unwinding of 5Ј-terminal secondary structure by the helicase eIF4A in concert with eIF4B and eIF4H, recognition of the 3Ј-terminal poly(A) tract by poly(A)-binding protein (PABP), and binding of eIF4G to the 40S ribosomal subunit through eIF3. Both the primary and secondary structure of the 5Ј-UTR are capable of modulating translational efficiency (4, 5). mRNAs containing short 5Ј-UTRs with little secondary structure or terminal oligopyrimidine tracts are more efficiently translated under normal conditions with a limited level of eIF4E. Translational efficiency is diminished in mRNAs containing long, GϩC-rich, and highly structured 5Ј-UTRs because of the necessity for energy-dependent unwinding prior to start codon recognition (6). Translation of these mRNAs requires high levels of eIF4F, the complex of eIF4E, eIF4A, and eIF4G (3, 7). The availability of eIF4E to enter the eIF4F complex is regulated by the PI3K/Akt/mTOR signaling cascade; eIF4E is sequestered by binding to the 4E-BPs, but activation of the mTOR kinase causes phosphorylation of the 4E-BPs and release of eIF4E (8, 9). The activity of eIF4E can be also regulated by phosphorylation via the mitogen-activat...

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Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells

Cited by 39 publications

References 59 publications

Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia

Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia

Synergistic effects of TGFβ2, WNT9a, and FGFR4 signals attenuate satellite cell differentiation during skeletal muscle development

Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5′-Terminal Cap and Hairpin

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