title: Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells.
abstract: The Ras/Raf/MAPK and PI3K/Akt/mTORC1 cascades are two most aberrantly regulated pathways in cancers. As MAPK-interacting kinases (Mnks) are part of the convergent node of these two pathways, and play a pivotal role in cellular transformation, targeting Mnks has emerged as a potential therapeutic strategy. Herein, a dual-specific Mnk1/2 inhibitor MNKI-57 and a potent Mnk2-specific inhibitor MNKI-4 were selected for a panel screen against 28 human cancer cell lines. The study reveals that MNKI-57 and MNKI-4 are most potent against leukemia cells KYO-1 (i.e. BC-CML) and KG-1 (i.e. AML). Interestingly, we found that sensitivity of selected leukemia cells to Mnk inhibitors is correlated with the level of phosphorylated 4E-BP1 at Thr70. The anti-proliferative effects of Mnk inhibitors are cytostatic in the sensitive KYO-1 cells, inducing significant G1 arrest via down-regulation of cyclin D1 expression. In KYO-1 cells where Akt is not constitutively active, Mnk inhibitors increase the sensitivity of cells to rapamycin, resulting in a more pronounced anti-proliferative activity. Remarkably, the synergistic anti-proliferative effects are associated with a marked de-phosphorylation of 4E-BP1 at Thr70. Collectively, these data highlight the importance of 4E-BP1 as a key integrator in the MAPK and mTORC1 cascades, and suggest that a combined pharmacologic inhibition of mTORC1 and Mnk kinases offers an innovative therapeutic opportunity in BC-CML.
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Centre for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Teo
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Centre for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Centre for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Centre for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Todd
authors.initials: T
authors.lastname: Gillam
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Centre for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Frankie
authors.initials: F
authors.lastname: Lam
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Centre for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sykes
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Centre for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia. Electronic address: shudong.wang@unisa.edu.au.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020014:K562 Cells; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D019938:Cyclin D1; D013912:Threonine; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; CGP57380; Cell cycle; Chronic myeloid leukemia; Mnk inhibitor; Rapamycin