RESUMO
The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The messenger RNA (mRNA) cap-binding protein eIF4E is an oncoprotein that has an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eukaryotic translation initiation factor 4E (eIF4E) cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that transforming growth factor-beta (TGFß) induces eIF4E phosphorylation to promote the translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFß requires translational activation via the non-canonical TGFß signaling branch acting through eIF4E phosphorylation.
Assuntos
Transição Epitelial-Mesenquimal , Fator de Iniciação 4E em Eucariotos/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 3 da Matriz/metabolismo , Fatores de Transcrição/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Transformação Celular Neoplásica/genética , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/metabolismo , Metaloproteinase 3 da Matriz/genética , Camundongos , Fosforilação , Biossíntese de Proteínas/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genéticaRESUMO
Cancer cells are characterized by aberrant growth arising from deregulated signalling pathways. The mammalian target of rapamycin (mTOR) pathway integrates multiple growth signals coming from both intracellular and extracellular cues. In this short review, we summarize what is known about the efficacy of targeting the mTOR pathway to treat cancer patients, and we explain the rationale behind promising new inhibitors that could show more potent tumour growth inhibition than did the first generation of these drugs.