RESUMEN
The basic understanding of the biological effects of eukaryotic translation initiation factors (EIFs) remains incomplete, notably for their roles independent of protein translation. Different EIFs exhibit nuclear localization and DNA-related functions have been proposed, but the understanding of EIFs novel functions beyond protein translation lacks of integrative analyses between the genomic and the proteomic levels. Here, the noncanonical function of EIF3F was studied in human lung adenocarcinoma by combining methods that revealed both the protein-protein and the protein-DNA interactions of this factor. We discovered that EIF3F promotes cell metastasis in vivo. The underpinning molecular mechanisms involved the regulation of a cluster of 34 metastasis-promoting genes including Snail2, as revealed by proteomics combined with immuno-affinity purification of EIF3F and ChIP-seq/Q-PCR analyses. The interaction between EIF3F and signal transducer and activator of transcription 3 (STAT3) controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion, which were specifically abrogated using the STAT3 inhibitor Nifuroxazide or knockdown approaches. Furthermore, EIF3F overexpression reprogrammed energy metabolism through the activation of AMP-activated protein kinase and the stimulation of oxidative phosphorylation. Our findings demonstrate the role of EIF3F in the molecular control of cell migration, invasion, bioenergetics, and metastasis. The discovery of a role for EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma could lead to the development of diagnosis and therapeutic strategies.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Núcleo Celular/metabolismo , Metabolismo Energético/genética , Factor 3 de Iniciación Eucariótica/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Factor de Transcripción STAT3/metabolismo , Células A549 , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Núcleo Celular/genética , Núcleo Celular/patología , Conjuntos de Datos como Asunto , Metabolismo Energético/efectos de los fármacos , Factor 3 de Iniciación Eucariótica/genética , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Hidroxibenzoatos/farmacología , Pulmón/citología , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Ratones , Mutación , Invasividad Neoplásica/genética , Nitrofuranos/farmacología , Fosforilación Oxidativa/efectos de los fármacos , ARN Interferente Pequeño/metabolismo , RNA-Seq , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Factores de Transcripción de la Familia Snail/genética , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pancreatic adenocarcinoma, highly resistant to all current anti-cancer treatments, necessitates new approaches promoting cell death. We hypothesized that combined actions of several Bioactive Food Components (BFCs) might provide specific lethal effect towards tumor cells, sparing healthy cells. Human tumor pancreatic cell lines were tested in vitro for sensitivity to resveratrol, capsaicin, piceatannol, and sulforaphane cytotoxic effects. Combination of two or three components showed striking synergetic effect with gemcitabine in vitro. Each BFC used alone did not affect pancreatic tumor growth in a preclinical in vivo model, whereas couples of BFCs had anti-tumor activity. In addition, tumor toxicity was similar using gemcitabine alone or a combination of BFCs and two thirds of gemcitabine dose. Moreover, BFCs enhanced fibrotic response as compared to gemcitabine treatment alone. Reactive oxygen species (ROS) and apoptosis increases were observed, while cell cycle was very mildly affected. This study raises the possibility to use BFCs as beneficial food complements in the therapy of pancreatic adenocarcinoma, especially for patients unable to receive full doses of chemotherapy.