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

Cancer Lett. 2015 Feb 28;357(2):612-23. doi: 10.1016/j.canlet.2014.12.029. Epub 2014 Dec 16.

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.

Keywords: Apoptosis; CGP57380; Cell cycle; Chronic myeloid leukemia; Mnk inhibitor; Rapamycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis / drug effects
  • Blast Crisis / genetics
  • Blast Crisis / metabolism
  • Blast Crisis / pathology
  • Blotting, Western
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cyclin D1 / metabolism
  • Drug Synergism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • K562 Cells
  • MCF-7 Cells
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Structure
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Threonine / genetics
  • Threonine / metabolism
  • U937 Cells

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Phosphoproteins
  • Cyclin D1
  • Threonine
  • MKNK1 protein, human
  • MKNK2 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases