TRANSLATION CONTROL · Regulation of selective translation via signal transduction pathways

Regulation of selective translation via signal transduction pathways

The overall rate of protein synthesis is an important determinant of cancer cell metabolism. Many previous observations have indicated that deregulated growth pathways are involved in the regulation of translation supporting cancer growth and survival. In addition, they can preferentially enhance the translation of carcinogenesis-associated mRNAs, including regulators of the cell cycle, apoptosis, angiogenesis and invasion. Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer with a median survival of approximately one year. In the last decade, genetic profiling of brain tumours has improved our understanding of gliomagenesis and led to the development of many targeted therapies based on molecular interference with deregulated signalling networks. Although many screens have characterised and proposed the targeting of deregulated signalling pathways for therapeutic interference, recent reports have identified therapy resistance based on the compensatory activation of alternative signalling pathways. In a search for novel molecular targets that could be therapeutically developed, our kinome-focused microarray analysis identified the MAP (mitogen-activated protein) kinase-interacting kinase 1 (MNK1) as an attractive theranostic candidate. The study analysed significantly elevated MNK1 expression in human brain tumour patients including its most aggressive form of GBM. Inhibition of MNK1 activity in human GBM cells by the small molecule CGP57380 suppressed proliferation and colony formation whereas concomitant targeting MNK1 pathways together with rapamycin accentuated growth inhibition and cell-cycle arrest revealing therapeutic implications for deadly brain tumours. Interestingly, MNK signalling is not crucial for normal growth; although, MNK activity is necessary for growth and survival under certain conditions in particular stresses or cancer states. Thus, our results together with the previously published data, promote elevated MNK activity in human glioblastoma as an attractive therapeutic target for two reasons. First, MNK signalling is not required for normal cell growth or development. Second, its inhibition may neutralise the cellular stress responses that aid cancer cell survival and are triggered by many therapies. MNK kinases can bind to translation initiation complexes and phosphorylate the cap-binding protein, translation initiation factor eIF4E. Recent key finding demonstrates that eIF4E phosphorylation at Ser209 by MNK kinases is required for eIF4E action in opposing apoptosis and promoting carcinogenesis in vivo. However, the mechanism of MNK-dependent regulation of translation quality and cancer progression has not been fully elucidated. To further characterise the role of MNK1 in glioblastoma, we analysed MNK1-regulated translation. Analysis of polysomal profiles revealed substantial inhibition of global translation in MNK1 inhibitor, CGP57380 and rapamycin-treated cells. Microarray analysis of total and polysomal RNA from MNK1-depleted GBM cells identified mRNAs involved in regulation of TGF-ß pathway. Translation of SMAD2 mRNA as well as TGF-ß-induced cell motility and vimentin expression was regulated by MNK1 signaling. Our expression analysis in GBM patients using tissue microarray revealed a positive correlation between the immunohistochemical staining of MNK1 and SMAD2. SMAD2 protein is one of the major signal transducers during TGF-ß pathway activation, which is thought to play a crucial role in tumor malignancy. Importantly, in many malignant tumours, TGF-ß acts as an oncogenic factor and high TGF-ß / SMAD activity in human glioma patients correlates with poor prognosis. In addition, non-canonical TGF-ß signaling pathways can activate ERKs and p38 kinases that phosphorylate and activate MNKs. In our study, TGF-ß induced ERK and p38 activity as well as MNK1 phosphorylation in GBM cells. Therefore, our data together with previous observations propose a model whereby activation of MNK1 and TGF-ß pathways and their mutual regulation support GBM progression. Taken together, our findings offer insights into how MNK1 pathways control translation of cancer-related mRNAs including SMAD2, a key component of the TGF-ß signalling pathway. Furthermore, they suggest MNK1-controlled translational pathways in targeted strategies to more effectively treat GBM. To read more about the project please visit: http://www.fmi.ch/news/releases/articles/hemmings.110315.html

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз