ABSTRACT
The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for many cancers with little known in osteosarcoma. This study evaluated the efficacy of eFT508, a highly selective inhibitor of MNK1/2, as single drug alone and in combination with paclitaxel in preclinical models of osteosarcoma. EFT508 is active against multiple osteosarcoma cell lines via inhibiting growth, survival and migration. It also demonstrates anti-osteosarcoma selectivity with much less toxicity on normal osteoblastic than osteosarcoma cells. Consistent with in vitro findings, eFT508 at non-toxic dose significantly arrested tumor growth in mice throughout the whole duration of treatment. Mechanistically, eEFT508 is highly effective in blocking eIF4E phosphorylation and eIF4E-mediated protein translation. Combination index shows that eFT508 and paclitaxel is synergistic in osteosarcoma cells. Our findings highlight the therapeutic value of MNK1/2 inhibition and suggest eFT508 as a promising candidate for the treatment of osteosarcoma.
Subject(s)
Bone Neoplasms , Drug Resistance, Neoplasm , Osteosarcoma , Animals , Mice , Cell Line, Tumor , Eukaryotic Initiation Factor-4E/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Paclitaxel , Phosphorylation , Protein Serine-Threonine Kinases/metabolismABSTRACT
Osteosarcoma (OS) is the most common primary bone cancer, and frequently leads to mortality as a result of rapid proliferation and metastasis. Recent data highlight the important role of microRNAs (miRs) in human cancers, including OS, providing a novel method for its diagnosis and treatment. In the present study, it was identified that miR4913p expression was frequently decreased in OS tissues and OS cell lines. Restored miR4913p expression suppressed the growth and invasion of OS cells. Bioinformatics and experimental analysis indicated that tetraspanin 1 (TSPAN1) is a direct target of miR4913p in OS. The TSPAN1 mRNA level was inversely associated with the miR4913p level in OS tissues and cell lines. Consistent with this, TSPAN1 knockdown inhibited the growth and invasion of OS cells. In conclusion, these data provide compelling evidence that miR4913p functions as a tumor suppressor in OS to attenuate the potential of growth and invasion by targeting TSPAN1.
