n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and Triple-Negative-Breast-Neoplasms

Protein synthesis has a key role in the control of cell proliferation, and its deregulation is associated with pathological conditions, notably cancer. Rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), was known to inhibit protein synthesis. However, it does not substantially inhibit protein synthesis and cell proliferation in many cancer types. We were interested in finding a novel target in rapamycin-resistant cancer. The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). Here, we provide evidence that glycogen synthase kinase (GSK)-3β promotes cell proliferation through positive regulation of protein synthesis. We found that GSK-3β phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis. Considering the clinical relevance of pathways regulating protein synthesis, our study provides a promising new strategy and target for cancer therapy.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Cycle Proteins; Cell Growth Processes; Enzyme Inhibitors; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Mice; Mice, Nude; Peptide Initiation Factors; Phosphoproteins; Phosphorylation; Protein Binding; Protein Biosynthesis; Random Allocation; Thiazoles; Triple Negative Breast Neoplasms; Urea; Xenograft Model Antitumor Assays