RESUMEN
Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Gotas Lipídicas , Proteínas Proto-Oncogénicas c-myc , Humanos , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Glutamina/metabolismo , Neoplasias Renales/patología , Gotas Lipídicas/efectos de los fármacos , Gotas Lipídicas/metabolismo , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Regulación hacia Arriba , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoRESUMEN
During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.
Asunto(s)
Neoplasias , Medicina de Precisión , Humanos , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Neuroblastoma (NB), a childhood tumor derived from the sympathetic nervous system, presents with heterogeneous clinical behavior. While some tumors regress spontaneously without medical intervention, others are resistant to therapy, associated with an aggressive phenotype. MYCN-amplification, frequently occurring in high-risk NB, is correlated with an undifferentiated phenotype and poor prognosis. Differentiation induction has been proposed as a therapeutic approach for high-risk NB. We have previously shown that MYCN maintains an undifferentiated state via regulation of the miR-17 ~ 92 microRNA cluster, repressing the nuclear hormone receptors (NHRs) estrogen receptor alpha (ERα) and the glucocorticoid receptor (GR). METHODS: Cell viability was determined by WST-1. Expression of differentiation markers was analyzed by Western blot, RT-qPCR, and immunofluorescence analysis. Metabolic phenotypes were studied using Agilent Extracellular Flux Analyzer, and accumulation of lipid droplets by Nile Red staining. Expression of angiogenesis, proliferation, and neuronal differentiation markers, and tumor sections were assessed by immunohistochemistry. Gene expression from NB patient as well as adrenal gland cohorts were analyzed using GraphPad Prism software (v.8) and GSEA (v4.0.3), while pseudo-time progression on post-natal adrenal gland cells from single-nuclei transcriptome data was computed using scVelo. RESULTS: Here, we show that simultaneous activation of GR and ERα potentiated induction of neuronal differentiation, reduced NB cell viability in vitro, and decreased tumor burden in vivo. This was accompanied by a metabolic reprogramming manifested by changes in the glycolytic and mitochondrial functions and in lipid droplet accumulation. Activation of the retinoic acid receptor alpha (RARα) with all-trans retinoic acid (ATRA) further enhanced the differentiated phenotype as well as the metabolic switch. Single-cell nuclei transcriptome analysis of human adrenal glands indicated a sequential expression of ERα, GR, and RARα during development from progenitor to differentiated chromaffin cells. Further, in silico analysis revealed that patients with higher combined expression of GR, ERα, and RARα mRNA levels had elevated expression of neuronal differentiation markers and a favorable outcome. CONCLUSION: Together, our findings suggest that combination therapy involving activation of several NHRs could be a promising pharmacological approach for differentiation treatment of NB patients.
Asunto(s)
Receptor alfa de Estrógeno , Neuroblastoma , Diferenciación Celular , Línea Celular Tumoral , Niño , Receptor alfa de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/patología , Pronóstico , Receptores Citoplasmáticos y Nucleares/metabolismo , Tretinoina/farmacologíaRESUMEN
Many metabolic pathways, including lipid metabolism, are rewired in tumors to support energy and biomass production and to allow adaptation to stressful environments. Neuroblastoma is the second deadliest solid tumor in children. Genetic aberrations, as the amplification of the MYCN-oncogene, correlate strongly with disease progression. Yet, there are only a few molecular targets successfully exploited in the clinic. Here we show that inhibition of fatty acid synthesis led to increased neural differentiation and reduced tumor burden in neuroblastoma xenograft experiments independently of MYCN-status. This was accompanied by reduced levels of the MYCN or c-MYC oncoproteins and activation of ERK signaling. Importantly, the expression levels of genes involved in de novo fatty acid synthesis showed prognostic value for neuroblastoma patients. Our findings demonstrate that inhibition of de novo fatty acid synthesis is a promising pharmacological intervention strategy for the treatment of neuroblastoma independently of MYCN-status.
RESUMEN
In pediatric neuroblastoma, MYCN-amplification correlates to poor clinical outcome and new treatment options are needed for these patients. Identifying the metabolic adaptations crucial for tumor progression may be a promising strategy to discover novel therapeutic targets. Here, we have combined proteomics, gene expression profiling, functional analysis, and metabolic tracing to decipher the impact of MYCN on neuroblastoma cell metabolism. We found that high MYCN levels are correlated with altered expression of proteins involved in multiple metabolic processes, including enhanced glycolysis and increased oxidative phosphorylation. Unexpectedly, we discovered that MYCN-amplified cells showed de novo glutamine synthesis. Furthermore, inhibition of ß-oxidation reduced the viability of MYCN-amplified cells in vitro and decreased tumor burden in vivo, while not affecting non-MYCN-amplified tumors. Our data provide information on metabolic processes in MYCN expressing tumors, which could be exploited for the development of novel targeted therapies.
RESUMEN
MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms' tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use.
RESUMEN
Accumulating evidence implicates mitochondrial and metabolic pathways in the establishment of pluripotency, as well as in the control of proliferation and differentiation programs. From classic studies in mouse embryos to the latest findings in adult stem cells, human embryonic and induced pluripotent stem cells, an increasing number of evidence suggests that mitochondrial and metabolic-related processes might intertwine with signaling networks and epigenetic rewiring, thereby modulating cell fate decisions. This review summarizes the progresses in this exciting field of research. Dissecting these complex mitochondrial and metabolic mechanisms may lead to a more comprehensive understanding of stemness biology and to potential improvements in stem cell applications for biomedicine, cell therapy, and disease modeling.
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Reprogramación Celular , Redes y Vías Metabólicas , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Animales , Proliferación Celular , Metabolismo Energético , Humanos , Mitocondrias/genética , Mitocondrias/metabolismoRESUMEN
Histamine (Hia) is the most multifunctional biogenic amine. It is synthetized by histidine decarboxylase (HDC) in a reduced set of mammalian cell types. Mast cells and histaminergic neurons store Hia in specialized organelles until the amine is extruded by exocytosis; however, other immune and cancer cells are able to produce but not store Hia. The intracellular effects of Hia are still not well characterized, in spite of its physiopathological relevance. Multiple functional relationships exist among Hia metabolism/signaling elements and those of other biogenic amines, including growth-related polyamines. Previously, we obtained the first insights for an inhibitory effect of newly synthetized Hia on both growth-related polyamine biosynthesis and cell cycle progression of non-fully differentiated mammalian cells. In this work, we describe progress in this line. HEK293 cells were transfected to express active and inactive versions of GFP-human HDC fusion proteins and, after cell sorting by flow cytometry, the relative expression of a large number of proteins associated with cell signaling were measured using an antibody microarray. Experimental results were analyzed in terms of protein-protein and functional interaction networks. Expression of active HDC induced a cell cycle arrest through the alteration of the levels of several proteins such as cyclin D1, cdk6, cdk7 and cyclin A. Regulation of α-synuclein and caspase-3 was also observed. The analyses provide new clues on the molecular mechanisms underlying the regulatory effects of intracellular newly synthetized Hia on cell proliferation/survival, cell trafficking and protein turnover. This information is especially interesting for emergent and orphan immune and neuroinflammatory diseases.
Asunto(s)
Caspasa 3/biosíntesis , Histamina/fisiología , Histidina Descarboxilasa/genética , alfa-Sinucleína/biosíntesis , Ciclo Celular , Proliferación Celular/efectos de los fármacos , Células HEK293 , Humanos , Transducción de Señal , TransfecciónRESUMEN
Tumor cells suffer a metabolic reprogramming which allows them to use metabolic fuels (glucose, glutamine, lipids) through anabolic fates to support their enhanced proliferation and other carcinogenesis-related features. The present review tries to address and summarize the broad and growing information available about this reprogramming, whose pieces, put together, make up a complex scheme that encompasses different complexity scales, from cells to systemic networks.