New insights into malignant cell survival mechanisms in medulloblastoma.

mRNA translation and protein synthesis is an important determinant for cell metabolism and cell homeostasis. Perturbations in cellular homeostasis often result in activation of negative feedback loops as compensatory mechanisms. Although, these mechanisms are important for mammalian cells to adjust to environmental changes, they also pose a major challenge for targeted cancer therapy as they provide escape mechanisms for cancer cells. The mammalian target of rapamycin (mTOR) is a crucial regulator of mRNA translation, protein synthesis and metabolism and represents an attractive target for anticancer therapy. We have recently reported that selective inhibition of mTORC1 by rapamycin or its analogs in medulloblastoma cells results in phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) on serine-209, an event known to be associated with induction of protein translation and cell transformation. We have also previously established that this event is mediated by mitogen-activated protein (MAP) kinase-interacting kinase 2 (Mnk2) independently of MAPKs, the conventional activators of Mnks. Here we discuss the implications for our current understanding of negative feedback regulation by mTOR and Mnk in cancer.