RESUMEN
Tumor cells undergo a metabolic shift toward specific bioenergetic (glycolysis) and anabolic (protein and lipid synthesis) processes that promote rapid growth. Nomura et al. (2010) now demonstrate that an increase in monoacylglycerol lipase (MAGL) drives tumorigenesis through the lipolytic release and remodeling of free fatty acids.
Asunto(s)
Metabolismo de los Lípidos , Monoacilglicerol Lipasas/metabolismo , Neoplasias/metabolismo , Ácidos Grasos/metabolismo , HumanosRESUMEN
Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell-intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. This is achieved through the activation of a transcriptional program affecting metabolic gene targets of hypoxia-inducible factor (HIF1alpha) and sterol regulatory element-binding protein (SREBP1 and SREBP2). We find that SREBP1 and 2 promote proliferation downstream of mTORC1, and the activation of these transcription factors is mediated by S6K1. Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Glucólisis/fisiología , Lípidos/biosíntesis , Vía de Pentosa Fosfato/fisiología , Biosíntesis de Proteínas/fisiología , Factores de Transcripción/metabolismo , Transcripción Genética/fisiología , Animales , Línea Celular Transformada , Proliferación Celular , Genómica/métodos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lípidos/genética , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolómica/métodos , Ratones , Complejos Multiproteicos , Neoplasias/genética , Neoplasias/metabolismo , Obesidad/genética , Obesidad/metabolismo , Proteínas , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Serina-Treonina Quinasas TOR , Factores de Transcripción/genéticaRESUMEN
The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient-sensitive protein kinase that is aberrantly activated in many human cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, which has been linked to environmental factors that affect mTORC1 activity, including diet. Ablation of the gene encoding TSC1 (tuberous sclerosis complex 1), which as part of the TSC1-TSC2 complex is an upstream inhibitor of mTORC1, results in constitutively increased mTORC1 signaling, an effect on this pathway similar to that of obesity. We found that mice with liver-specific knockout of Tsc1 developed sporadic hepatocellular carcinoma with heterogeneous histological and biochemical features. The spontaneous development of hepatocellular carcinoma in this mouse model was preceded by a series of pathological changes that accompany the primary etiologies of this cancer in humans, including liver damage, inflammation, necrosis, and regeneration. Chronic mTORC1 signaling led to unresolved endoplasmic reticulum stress and defects in autophagy, factors that contributed to hepatocyte damage and hepatocellular carcinoma development. Therefore, we conclude that increased activation of mTORC1 can promote carcinogenesis and may thus represent a key molecular link between cancer risk and environmental factors, such as diet.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas/metabolismo , Factores de Transcripción/metabolismo , Animales , Antibióticos Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Células Cultivadas , Progresión de la Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Hepatocitos/metabolismo , Hepatocitos/patología , Immunoblotting , Inmunohistoquímica , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complejos Multiproteicos/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/fisiología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
As a key regulator of cell growth and proliferation, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) has been the subject of intense investigation for its role in tumor development and progression. This research has revealed a signaling network of oncogenes and tumor suppressors lying upstream of mTORC1, and oncogenic perturbations to this network result in the aberrant activation of this kinase complex in the majority of human cancers. However, the molecular events downstream of mTORC1 contributing to tumor cell growth and proliferation are just coming to light. In addition to its better-known functions in promoting protein synthesis and suppressing autophagy, mTORC1 has emerged as a key regulator of cellular metabolism. Recent studies have found that mTORC1 activation is sufficient to stimulate an increase in glucose uptake, glycolysis, and de novo lipid biosynthesis, which are considered metabolic hallmarks of cancer, as well as the pentose phosphate pathway. Here, we focus on the molecular mechanisms of metabolic regulation by mTORC1 and the potential consequences for anabolic tumor growth and therapeutic strategies.
Asunto(s)
Neoplasias/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/fisiología , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Modelos Biológicos , Complejos Multiproteicos , Neoplasias/genética , Proteínas/genética , Proteínas/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Serina-Treonina Quinasas TORRESUMEN
Tumor cells are characterized by adaptations in cellular metabolism that afford growth and proliferative advantages over normal cells and, thus, contribute to cancer pathophysiology. There is an increasing appreciation of the fact that oncogenic signaling controls the metabolic reprogramming of cancer cells; however, the mechanisms and critical players are only beginning to be elucidated. Recent studies have revealed that mTOR complex 1 (mTORC1), a master regulator of cell growth and proliferation downstream of oncogenic signaling pathways, controls specific aspects of cellular metabolism through the induction of metabolic gene expression. mTORC1 activation is sufficient to promote flux through glycolysis and the oxidative branch of the pentose phosphate pathway, as well as to stimulate de novo lipogenesis, all processes that are important in tumor biology. As mTORC1 signaling is aberrantly elevated in the majority of genetic tumor syndromes and sporadic cancers, this pathway is poised to be a major driver of the metabolic conversion of tumor cells.
Asunto(s)
Serina-Treonina Quinasas TOR/metabolismo , Animales , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos , Proteínas/genética , Proteínas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Transcripción GenéticaRESUMEN
Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.
Asunto(s)
Hepatocitos/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Células Cultivadas , Insulina/metabolismo , Lipogénesis , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Complejos Multiproteicos , Proteínas/fisiología , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/antagonistas & inhibidores , Serina-Treonina Quinasas TOR , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1-deficient malignancies and Kras/p53 mutant lung cancer. We show that agents that enhance proteotoxic stress, including the HSP90 inhibitor IPI-504, induce tumor regression in aggressive mouse models, but only when combined with rapamycin. These agents synergize by promoting irresolvable ER stress, resulting in catastrophic ER and mitochondrial damage. This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations.