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1.
Nature ; 615(7953): 705-711, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36922598

RESUMEN

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years1. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners2-5. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8+ T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders.


Asunto(s)
Sacarosa , Edulcorantes , Linfocitos T , Animales , Ratones , Sacarosa/análogos & derivados , Edulcorantes/administración & dosificación , Edulcorantes/efectos adversos , Edulcorantes/farmacología , Edulcorantes/uso terapéutico , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Inocuidad de los Alimentos , Señalización del Calcio/efectos de los fármacos , Receptores de Antígenos de Linfocitos T/efectos de los fármacos , Receptores de Antígenos de Linfocitos T/inmunología , Infecciones Bacterianas/inmunología , Neoplasias/inmunología , Autoinmunidad/efectos de los fármacos , Autoinmunidad/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología
2.
Nat Cancer ; 5(5): 701-715, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38698089

RESUMEN

Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection.


Asunto(s)
Ácido Fólico , Mitocondrias , Neoplasias , Humanos , Ácido Fólico/metabolismo , Neoplasias/metabolismo , Mitocondrias/metabolismo , Animales , Formiatos/metabolismo , Microambiente Tumoral , Metástasis de la Neoplasia
3.
Sci Adv ; 9(36): eadh2023, 2023 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-37672588

RESUMEN

Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.


Asunto(s)
Neoplasias , Prolina , Aminoácidos , Transporte Biológico , Matriz Extracelular , Macrófagos
4.
Cell Rep ; 42(6): 112562, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37245210

RESUMEN

Mitochondrial 10-formyltetrahydrofolate (10-formyl-THF) is utilized by three mitochondrial enzymes to produce formate for nucleotide synthesis, NADPH for antioxidant defense, and formyl-methionine (fMet) to initiate mitochondrial mRNA translation. One of these enzymes-aldehyde dehydrogenase 1 family member 2 (ALDH1L2)-produces NADPH by catabolizing 10-formyl-THF into CO2 and THF. Using breast cancer cell lines, we show that reduction of ALDH1L2 expression increases ROS levels and the production of both formate and fMet. Both depletion of ALDH1L2 and direct exposure to formate result in enhanced cancer cell migration that is dependent on the expression of the formyl-peptide receptor (FPR). In various tumor models, increased ALDH1L2 expression lowers formate and fMet accumulation and limits metastatic capacity, while human breast cancer samples show a consistent reduction of ALDH1L2 expression in metastases. Together, our data suggest that loss of ALDH1L2 can support metastatic progression by promoting formate and fMet production, resulting in enhanced FPR-dependent signaling.


Asunto(s)
Neoplasias de la Mama , Formiatos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH , Femenino , Humanos , Neoplasias de la Mama/metabolismo , Formiatos/metabolismo , Metionina , NADP , Especies Reactivas de Oxígeno , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo
5.
Front Immunol ; 12: 637960, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33868263

RESUMEN

Regulatory T cells (Tregs) are essential for mitigating inflammation. Tregs are found in nearly every tissue and play either beneficial or harmful roles in the host. The availability of various nutrients can either enhance or impair Treg function. Mitochondrial oxidative metabolism plays a major role in supporting Treg differentiation and fitness. While Tregs rely heavily on oxidation of fatty acids to support mitochondrial activity, they have found ways to adapt to different tissue types, such as tumors, to survive in competitive environments. In addition, metabolic by-products from commensal organisms in the gut also have a profound impact on Treg differentiation. In this review, we will focus on the core metabolic pathways engaged in Tregs, especially in the context of tissue nutrient environments, and how they can affect Treg function, stability and differentiation.


Asunto(s)
Inflamación/inmunología , Microbiota/fisiología , Mitocondrias/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Humanos , Inmunomodulación , Nutrientes , Oxidación-Reducción
6.
Nat Commun ; 12(1): 6176, 2021 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-34702840

RESUMEN

Serine is a non-essential amino acid that is critical for tumour proliferation and depletion of circulating serine results in reduced tumour growth and increased survival in various cancer models. While many cancer cells cultured in a standard tissue culture medium depend on exogenous serine for optimal growth, here we report that these cells are less sensitive to serine/glycine depletion in medium containing physiological levels of metabolites. The lower requirement for exogenous serine under these culture conditions reflects both increased de novo serine synthesis and the use of hypoxanthine (not present in the standard medium) to support purine synthesis. Limiting serine availability leads to increased uptake of extracellular hypoxanthine, sparing available serine for other pathways such as glutathione synthesis. Taken together these results improve our understanding of serine metabolism in physiologically relevant nutrient conditions and allow us to predict interventions that may enhance the therapeutic response to dietary serine/glycine limitation.


Asunto(s)
Neoplasias/metabolismo , Serina/metabolismo , Vías Biosintéticas , Línea Celular Tumoral , Proliferación Celular , Medios de Cultivo/química , Medios de Cultivo/metabolismo , Glicina/análisis , Glicina/metabolismo , Humanos , Hipoxantina/análisis , Hipoxantina/metabolismo , Neoplasias/dietoterapia , Neoplasias/patología , Purinas/biosíntesis , Serina/análisis , Regulación hacia Arriba
7.
Cell Rep ; 34(7): 108750, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33596424

RESUMEN

Inter-cellular heterogeneity in metabolic state has been proposed to influence many cancer phenotypes, including responses to targeted therapy. Here, we track the transitions and heritability of metabolic states in single PIK3CA mutant breast cancer cells, identify non-genetic glycolytic heterogeneity, and build on observations derived from methods reliant on bulk analyses. Using fluorescent biosensors in vitro and in tumors, we have identified distinct subpopulations of cells whose glycolytic and mitochondrial metabolism are regulated by combinations of phosphatidylinositol 3-kinase (PI3K) signaling, bromodomain activity, and cell crowding effects. The actin severing protein cofilin, as well as PI3K, regulates rapid changes in glucose metabolism, whereas treatment with the bromodomain inhibitor slowly abrogates a subpopulation of cells whose glycolytic activity is PI3K independent. We show how bromodomain function and PI3K signaling, along with actin remodeling, independently modulate glycolysis and how targeting these pathways affects distinct subpopulations of cancer cells.


Asunto(s)
Glucólisis/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Análisis de la Célula Individual/métodos , Línea Celular Tumoral , Proliferación Celular , Heterogeneidad Genética , Humanos
8.
Nat Commun ; 12(1): 366, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33446657

RESUMEN

Many tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet.


Asunto(s)
Glicina/metabolismo , Neoplasias/dietoterapia , Serina/biosíntesis , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Glicina/análisis , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias/enzimología , Neoplasias/metabolismo , Neoplasias/fisiopatología , Fosfoglicerato-Deshidrogenasa/metabolismo , Serina/análisis
9.
Cell Rep ; 30(2): 481-496.e6, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31940491

RESUMEN

Loss of p53 function contributes to the development of many cancers. While cell-autonomous consequences of p53 mutation have been studied extensively, the role of p53 in regulating the anti-tumor immune response is still poorly understood. Here, we show that loss of p53 in cancer cells modulates the tumor-immune landscape to circumvent immune destruction. Deletion of p53 promotes the recruitment and instruction of suppressive myeloid CD11b+ cells, in part through increased expression of CXCR3/CCR2-associated chemokines and macrophage colony-stimulating factor (M-CSF), and attenuates the CD4+ T helper 1 (Th1) and CD8+ T cell responses in vivo. p53-null tumors also show an accumulation of suppressive regulatory T (Treg) cells. Finally, we show that two key drivers of tumorigenesis, activation of KRAS and deletion of p53, cooperate to promote immune tolerance.


Asunto(s)
Células Mieloides/metabolismo , Linfocitos T Reguladores/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Humanos , Ratones
10.
Cancer Immunol Res ; 5(8): 695-709, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28765120

RESUMEN

Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. IDO1 is an immunosuppressive enzyme that degrades tryptophan. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE2), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways. COX-2 expression itself depends on the MAPK pathway, which therefore indirectly controls IDO1 expression. Most of these tumors carry PI3K or MAPK oncogenic mutations, which may favor constitutive IDO1 expression. Celecoxib treatment promoted immune rejection of IDO1-expressing human tumor xenografts in immunodeficient mice reconstituted with human allogeneic lymphocytes. This effect was associated with a reduced expression of IDO1 in those ovarian SKOV3 tumors and an increased infiltration of CD3+ and CD8+ cells. Our results highlight the role of COX-2 in constitutive IDO1 expression by human tumors and substantiate the use of COX-2 inhibitors to improve the efficacy of cancer immunotherapy, by reducing constitutive IDO1 expression, which contributes to the lack of T-cell infiltration in "cold" tumors, which fail to respond to immunotherapy. Cancer Immunol Res; 5(8); 695-709. ©2017 AACR.


Asunto(s)
Ciclooxigenasa 2/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Celecoxib/administración & dosificación , Línea Celular Tumoral , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/genética , Dinoprostona/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Ratones , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
11.
PLoS One ; 10(4): e0122517, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25853464

RESUMEN

Loss of expression of surface antigens represents a significant problem for cancer immunotherapy. Microphthalmia-associated transcription factor (MITF-M) regulates melanocyte fate by driving expression of many differentiation genes, whose protein products can be recognized by cytolytic T lymphocytes. We previously reported that interleukin-1ß (IL-1ß) can downregulate MITF-M levels. Here we show that downregulation of MITF-M expression by IL-1ß was paralleled by an upregulation of miR-155 expression in four melanoma lines. We confirmed that miR-155 was able to target endogenous MITF-M in melanoma cells and demonstrated a role for miR-155 in the IL-1ß-induced repression of MITF-M by using an antagomiR. Notably, we also observed a strong negative correlation between MITF-M and miR-155 levels in a mouse model of melanoma. Taken together, our results indicate that MITF-M downregulation by inflammatory stimuli might be partly due to miR-155 upregulation. This could represent a novel mechanism of melanoma immune escape in an inflammatory microenvironment.


Asunto(s)
Interleucina-1beta/genética , Melanoma/genética , MicroARNs/genética , Factor de Transcripción Asociado a Microftalmía/biosíntesis , Animales , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Interleucina-1beta/metabolismo , Melanoma/patología , Ratones , MicroARNs/biosíntesis , Factor de Transcripción Asociado a Microftalmía/genética
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