Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells. Issue 2 (28th February 2015)

• Record Type: Journal Article
• Authors: Teo, Theodosia; Yu, Mingfeng; Yang, Yuchao; Gillam, Todd; Lam, Frankie; Sykes, Matthew J.; Wang, Shudong
• Is Part Of: Cancer letters. Volume 357:Issue 2(2015)
• Page Start: 612
• Page End: 623
• Publication Date: 2015-02-28
• Subjects: 4E-BP eukaryotic initiation factor 4E-binding protein -- Akt Ak thymoma -- AML acute myeloid leukemia -- BC-CML blast crisis-chronic myeloid leukemia -- Bcl-2 B-cell lymphoma-2 -- BCR-ABL breakpoint cluster region-abelson -- CDK cyclin-dependent kinase -- del deletion -- eIF eukaryotic initiation factor -- ERα estrogen receptor α -- ERK extracellular-signal-regulated kinase -- FACS fluorescence-activated cell sorting -- FITC fluorescein isothiocyanate -- FLT3-ITD feline McDonough sarcoma-like tyrosine kinase-3-internal tandem duplication -- GI50 50% growth inhibition -- GTP guanosine triphosphate -- HER2 human epidermal growth factor receptor 2 -- MAPK mitogen-activated protein kinase -- Mcl-1 myeloid cell leukemia-1 -- Mnk mitogen-activated protein kinase-interacting kinase -- mTORC1 mammalian target of rapamycin complex 1 -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- mut mutation -- PARP poly(ADP-ribose)polymerase -- PI propidium iodide -- PI3K phosphatidylinositol 3-kinase -- PKC protein kinase C -- PTEN phosphatase and tensin homolog -- qRT-PCR quantitative reverse transcription–polymerase chain reaction -- Raf rapidly accelerated fibrosarcoma -- Ras rat sarcoma -- Rb retinoblastoma protein -- Rheb Ras homolog enriched in brain -- RNA ribonucleic acid -- rpS6 ribosomal protein S6 -- SD standard deviation -- siRNA small interfering ribonucleic acid -- TSC tuberous sclerosis complex -- wt wild-type; Apoptosis -- Chronic myeloid leukemia -- CGP57380 -- Cell cycle -- Mnk inhibitor -- Rapamycin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2014.12.029
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Mnk inhibitors are mostly potent against cancer cells with a high ratio of p-4E-BP1 T70 :4E-BP1. Mnk inhibitors increase the sensitivity of leukemia KYO-1 cells to rapamycin. Co-inhibition of mTORC1 and Mnks reduces cell proliferation associated with the de-phosphorylation of 4E-BP1 at Thr70. 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.