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
Darinaparsin (Dar) is a more potent cytotoxic arsenical than arsenic trioxide (ATO). We hypothesized that the increased cytotoxicity of Dar may be because of a decreased cytoprotective response. We observed that, unlike ATO, Dar does not induce heme oxygenase-1 (HO-1), even though it induces expression of other nuclear factor (erythroid-derived 2)-like 2 (NRF2)-dependent detoxifying enzymes to a greater extent than ATO, in both cancer cell lines and patient-derived leukemic cells. This strengthens the emerging evidence, showing that response to reactive oxygen species (ROS) is stimuli specific. Dar treatment prevents recruitment of the transcriptional coregulator Brahma-related gene 1 (BRG1) to the HMOX1 promoter, which is required for HMOX1 expression. The inability of Dar to induce HO-1 correlates with arrest in G2/M cell cycle phase and BRG1 phosphorylation. Inhibition of HO-1 increases the toxicity of ATO, but has no effect on Dar-induced apoptosis. Accordingly, the lack of HO-1 induction is involved in Dar's enhanced antileukemic properties. Our data highlight cytoprotective responses mediated by HO-1 and BRG1 as a novel target for enhancing the therapeutic range of arsenicals.
