RESUMEN
Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.
Asunto(s)
Acetil-CoA Carboxilasa , Proteínas Adaptadoras Transductoras de Señales , Proteínas de Ciclo Celular , Supervivencia Celular , Ácidos Grasos , Glucosa , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Glucosa/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Acetil-CoA Carboxilasa/genética , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ácidos Grasos/metabolismo , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Ratones , NADP/metabolismo , Biosíntesis de Proteínas , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Estrés Oxidativo , Línea Celular Tumoral , Factores Eucarióticos de Iniciación/metabolismo , Factores Eucarióticos de Iniciación/genéticaRESUMEN
Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+] and response to [eCa2+] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+ AML versus BCR-ABL1+ leukaemias. Deficiency of CaSR reduces AML leukaemic stem cells (LSC) 6.5-fold. CaSR interacts with filamin A, a crosslinker of actin filaments, affects stemness-associated factors and modulates pERK, ß-catenin and c-MYC signaling and intracellular levels of [Ca2+] in MLL-AF9+ AML cells. Combination treatment of cytarabine plus CaSR-inhibition in various models may be superior to cytarabine alone. Our studies suggest CaSR to be a differential and targetable factor in leukaemia progression influencing self-renewal of AML LSC via [eCa2+] cues from the BMM.
Asunto(s)
Leucemia Mieloide Aguda , Receptores Sensibles al Calcio , Humanos , Receptores Sensibles al Calcio/genética , Proteínas Proto-Oncogénicas c-myc , Calcio , Proteínas de Fusión Oncogénica/metabolismo , Transducción de Señal , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Citarabina , Microambiente TumoralRESUMEN
Neuroblastoma (NB) accounts for 15% of cancer-related deaths in childhood despite considerable therapeutic improvements. While several risk factors, including MYCN amplification and alterations in RAS and p53 pathway genes, have been defined in NB, the clinical outcome is very variable and difficult to predict. Since genes of the mechanistic target of rapamycin (mTOR) pathway are upregulated in MYCN-amplified NB, we aimed to define the predictive value of the mTOR substrate-encoding gene eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) expression in NB patients. Using publicly available data sets, we found that EIF4EBP1 mRNA expression is positively correlated with MYCN expression and elevated in stage 4 and high-risk NB patients. In addition, high EIF4EBP1 mRNA expression is associated with reduced overall and event-free survival in the entire group of NB patients in three cohorts, as well as in stage 4 and high-risk patients. This was confirmed by monitoring the clinical value of 4EBP1 protein expression, which revealed that high levels of 4EBP1 are significantly associated with prognostically unfavorable NB histology. Finally, functional analyses revealed that EIF4EBP1 expression is transcriptionally controlled by MYCN binding to the EIF4EBP1 promoter in NB cells. Our data highlight that EIF4EBP1 is a direct transcriptional target of MYCN whose high expression is associated with poor prognosis in NB patients. Therefore, EIF4EBP1 may serve to better stratify patients with NB.