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1.
Nat Rev Mol Cell Biol ; 22(1): 22-38, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33188273

RESUMEN

Mechanical forces shape cells and tissues during development and adult homeostasis. In addition, they also signal to cells via mechanotransduction pathways to control cell proliferation, differentiation and death. These processes require metabolism of nutrients for both energy generation and biosynthesis of macromolecules. However, how cellular mechanics and metabolism are connected is still poorly understood. Here, we discuss recent evidence indicating how the mechanical cues exerted by the extracellular matrix (ECM), cell-ECM and cell-cell adhesion complexes influence metabolic pathways. Moreover, we explore the energy and metabolic requirements associated with cell mechanics and ECM remodelling, implicating a reciprocal crosstalk between cell mechanics and metabolism.


Asunto(s)
Matriz Extracelular/metabolismo , Homeostasis , Mecanotransducción Celular , Redes y Vías Metabólicas , Animales , Adhesión Celular , Diferenciación Celular , Humanos
3.
Br J Cancer ; 129(10): 1546-1557, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37689804

RESUMEN

Fumarate hydratase (FH) is an enzyme of the Tricarboxylic Acid (TCA) cycle whose mutations lead to hereditary and sporadic forms of cancer. Although more than twenty years have passed since its discovery as the leading cause of the cancer syndrome Hereditary leiomyomatosis and Renal Cell Carcinoma (HLRCC), it is still unclear how the loss of FH causes cancer in a tissue-specific manner and with such aggressive behaviour. It has been shown that FH loss, via the accumulation of FH substrate fumarate, activates a series of oncogenic cascades whose contribution to transformation is still under investigation. In this review, we will summarise these recent findings in an integrated fashion and put forward the case that understanding the biology of FH and how its mutations promote transformation will be vital to establish novel paradigms of oncometabolism.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Neoplasias Uterinas , Femenino , Humanos , Fumarato Hidratasa/genética , Neoplasias Uterinas/genética , Neoplasias Cutáneas/genética , Síndromes Neoplásicos Hereditarios/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología
4.
Nature ; 547(7661): 109-113, 2017 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-28658205

RESUMEN

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.


Asunto(s)
Adenosilmetionina Descarboxilasa/metabolismo , Complejos Multiproteicos/metabolismo , Poliaminas/metabolismo , Neoplasias de la Próstata/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adenosilmetionina Descarboxilasa/inmunología , Animales , Proliferación Celular , Activación Enzimática , Everolimus/uso terapéutico , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Metabolómica , Ratones , Complejos Multiproteicos/antagonistas & inhibidores , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Estabilidad Proteica , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
5.
Methods ; 77-78: 25-30, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25697760

RESUMEN

Prostate cancer is among the most frequent cancers in men, and despite its high rate of cure, the high number of cases results in an elevated mortality worldwide. Importantly, prostate cancer incidence is dramatically increasing in western societies in the past decades, suggesting that this type of tumor is exquisitely sensitive to lifestyle changes. Prostate cancer frequently exhibits alterations in the PTEN gene (inactivating mutations or gene deletions) or at the protein level (reduced protein expression or altered sub-cellular compartmentalization). The relevance of PTEN in this type of cancer is further supported by the fact that the sole deletion of PTEN in the murine prostate epithelium recapitulates many of the features of the human disease. In order to study the molecular alterations in prostate cancer, we need to overcome the methodological challenges that this tissue imposes. In this review we present protocols and methods, using PTEN as proof of concept, to study different molecular characteristics of prostate cancer.


Asunto(s)
Fosfohidrolasa PTEN/análisis , Fosfohidrolasa PTEN/biosíntesis , Neoplasias de la Próstata/metabolismo , Proteínas Supresoras de Tumor/análisis , Proteínas Supresoras de Tumor/biosíntesis , Animales , Humanos , Masculino , Ratones , Mutación/genética , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Supresoras de Tumor/genética
6.
Cell Rep ; 42(7): 112751, 2023 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-37405921

RESUMEN

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a cancer syndrome caused by inactivating germline mutations in fumarate hydratase (FH) and subsequent accumulation of fumarate. Fumarate accumulation leads to profound epigenetic changes and the activation of an anti-oxidant response via nuclear translocation of the transcription factor NRF2. The extent to which chromatin remodeling shapes this anti-oxidant response is currently unknown. Here, we explored the effects of FH loss on the chromatin landscape to identify transcription factor networks involved in the remodeled chromatin landscape of FH-deficient cells. We identify FOXA2 as a key transcription factor that regulates anti-oxidant response genes and subsequent metabolic rewiring cooperating without direct interaction with the anti-oxidant regulator NRF2. The identification of FOXA2 as an anti-oxidant regulator provides additional insights into the molecular mechanisms behind cell responses to fumarate accumulation and potentially provides further avenues for therapeutic intervention for HLRCC.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Neoplasias Uterinas , Femenino , Humanos , Fumarato Hidratasa/genética , Antioxidantes , Factor 2 Relacionado con NF-E2/genética , Leiomiomatosis/genética , Neoplasias Uterinas/genética , Neoplasias Cutáneas/genética , Síndromes Neoplásicos Hereditarios/genética , Cromatina , Neoplasias Renales/genética , Carcinoma de Células Renales/genética , Factor Nuclear 3-beta del Hepatocito/genética
7.
Sci Adv ; 8(42): eabq8297, 2022 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-36269833

RESUMEN

Fumarate hydratase (FH) is a mitochondrial enzyme that catalyzes the reversible hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle. Germline mutations of FH lead to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a cancer syndrome characterized by a highly aggressive form of renal cancer. Although HLRCC tumors metastasize rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas. How Fh1-deficient cells overcome these tumor-suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR-Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of the histone cell cycle regulator (HIRA) enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.

8.
Nat Metab ; 4(3): 327-343, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35288722

RESUMEN

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid ß-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism.


Asunto(s)
Adiposidad , Células Endoteliales , Animales , Células Endoteliales/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Poliaminas
9.
Cell Death Differ ; 27(4): 1186-1199, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31570853

RESUMEN

Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.


Asunto(s)
Senescencia Celular , Proteína de la Leucemia Promielocítica/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Animales , Línea Celular Tumoral , Proliferación Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Silenciador del Gen , Humanos , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo
10.
J Exp Med ; 217(6)2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32219437

RESUMEN

Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.


Asunto(s)
Neoplasias de la Próstata/enzimología , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Quinasas Activadas por AMP , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Epitelio/enzimología , Epitelio/patología , Células HEK293 , Heterocigoto , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Proteínas Mutantes/metabolismo , Metástasis de la Neoplasia , Fosfohidrolasa PTEN/metabolismo , Próstata/enzimología , Próstata/patología , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/metabolismo
11.
Cancer Res ; 79(24): 6153-6165, 2019 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-31594836

RESUMEN

The PPARγ coactivator 1 alpha (PGC1α) is a prostate tumor suppressor that controls the balance between anabolism and catabolism. PGC1A downregulation in prostate cancer is causally associated with the development of metastasis. Here we show that the transcriptional complex formed by PGC1α and estrogen-related receptor 1 alpha (ERRα) controls the aggressive properties of prostate cancer cells. PGC1α expression significantly decreased migration and invasion of various prostate cancer cell lines. This phenotype was consistent with remarkable cytoskeletal remodeling and inhibition of integrin alpha 1 and beta 4 expression, both in vitro and in vivo. CRISPR/Cas9-based deletion of ERRα suppressed PGC1α regulation of cytoskeletal organization and invasiveness. Mechanistically, PGC1α expression decreased MYC levels and activity prior to inhibition of invasiveness. In addition, PGC1α and ERRα associated at the MYC promoter, supporting the inhibitory activity PGC1α. The inverse correlation between PGC1α-ERRα activity and MYC levels was corroborated in multiple prostate cancer datasets. Altogether, these results support that PGC1α-ERRα functions as a tumor-suppressive transcriptional complex through the regulation of metabolic and signaling events. SIGNIFICANCE: These findings describe how downregulation of the prostate tumor suppressor PGC1 drives invasiveness and migration of prostate cancer cells.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-myc/genética , Receptores de Estrógenos/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Conjuntos de Datos como Asunto , Humanos , Masculino , Invasividad Neoplásica/genética , Regiones Promotoras Genéticas/genética , Neoplasias de la Próstata/patología , Transducción de Señal/genética , Transcripción Genética , Receptor Relacionado con Estrógeno ERRalfa
12.
Cell Death Dis ; 9(10): 1041, 2018 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-30310055

RESUMEN

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.


Asunto(s)
Factor de Transcripción Asociado a Microftalmía/genética , Neoplasias de la Próstata/genética , Transcriptoma/genética , Proteínas Supresoras de Tumor/genética , Animales , Línea Celular Tumoral , Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Ratones , Ratones Desnudos , Células PC-3 , Pronóstico , Neoplasias de la Próstata/patología , Factores de Transcripción/genética , Cadena B de alfa-Cristalina/genética
13.
Oncotarget ; 9(2): 1494-1504, 2018 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-29416709

RESUMEN

Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.

14.
Cancer Res ; 78(2): 399-409, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29187400

RESUMEN

The nuclear receptor PPAR-ß/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation, and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here, we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a noncanonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 with prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.Significance: These findings challenge the presumption that the function of the nuclear receptor PPARß/δ in cancer is dictated by ligand-mediated activation. Cancer Res; 78(2); 399-409. ©2017 AACR.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , PPAR delta/metabolismo , Neoplasias de la Próstata/patología , Factor Trefoil-1/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Regulación hacia Abajo , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , PPAR delta/genética , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Factor Trefoil-1/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Trends Endocrinol Metab ; 28(10): 748-757, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28938972

RESUMEN

Altered metabolism is a distinct feature of cancer cells. During transformation, the entire metabolic network is rewired to efficiently convert nutrients to biosynthetic precursors to sustain cancer cell growth and proliferation. Whilst the molecular underpinnings of this metabolic reprogramming have been described, its role in tumor progression is still under investigation. Importantly, the mitochondrion is a central actor in many of the metabolic processes that are altered in tumors. Yet, we have only begun to understand the dualities of mitochondrial function during cancer metastasis and therapy resistance. Paradoxically, mitochondrial metabolism can be both advantageous and detrimental to these processes, highlighting the need for a better understanding of the molecular and microenvironmental cues that define the role of this fascinating organelle. In this review article, we present an updated view on the different mitochondrial metabolic strategies adopted by cancer cells to overcome the many hurdles faced during tumor progression.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Mitocondrias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Animales , Progresión de la Enfermedad , Metabolismo Energético/fisiología , Humanos , Redes y Vías Metabólicas/fisiología
17.
Oncotarget ; 7(6): 6835-46, 2016 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-26771841

RESUMEN

Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa.


Asunto(s)
Biomarcadores de Tumor/genética , Biomarcadores de Tumor/orina , Cadherinas/genética , Cadherinas/orina , Vesículas Extracelulares/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/orina , Exosomas/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patología , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Neoplasias de la Próstata/patología
18.
Nat Commun ; 7: 12595, 2016 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-27553708

RESUMEN

Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.


Asunto(s)
Neoplasias de la Mama/secundario , Neoplasias de la Mama/terapia , Proteína de la Leucemia Promielocítica/antagonistas & inhibidores , Proteína de la Leucemia Promielocítica/metabolismo , Animales , Trióxido de Arsénico , Arsenicales/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Células MCF-7 , Ratones , Invasividad Neoplásica/genética , Óxidos/farmacología , Regiones Promotoras Genéticas , Proteína de la Leucemia Promielocítica/genética , Factor de Transcripción SOX9/genética , Factor de Transcripción STAT3/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Nat Cell Biol ; 18(6): 645-656, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27214280

RESUMEN

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.


Asunto(s)
Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Modelos Animales de Enfermedad , Metabolismo Energético/fisiología , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Ratones , Metástasis de la Neoplasia/patología , Neoplasias de la Próstata/patología , Receptores de Estrógenos/metabolismo , Receptor Relacionado con Estrógeno ERRalfa
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