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1.
Proc Natl Acad Sci U S A ; 121(13): e2319686121, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38507452

RESUMEN

Orphan solute carrier (SLC) represents a group of membrane transporters whose exact functions and substrate specificities are not known. Elucidating the function and regulation of orphan SLC transporters is not only crucial for advancing our knowledge of cellular and molecular biology but can potentially lead to the development of new therapeutic strategies. Here, we provide evidence for the biological function of a ubiquitous orphan lysosomal SLC, the Major Facilitator Superfamily Domain-containing Protein 1 (MFSD1), which has remained phylogenetically unassigned. Targeted metabolomics revealed that dipeptides containing either lysine or arginine residues accumulate in lysosomes of cells lacking MFSD1. Whole-cell patch-clamp electrophysiological recordings of HEK293-cells expressing MFSD1 on the cell surface displayed transport affinities for positively charged dipeptides in the lower mM range, while dipeptides that carry a negative net charge were not transported. This was also true for single amino acids and tripeptides, which MFSD1 failed to transport. Our results identify MFSD1 as a highly selective lysosomal lysine/arginine/histidine-containing dipeptide exporter, which functions as a uniporter.


Asunto(s)
Lisina , Proteínas de Transporte de Membrana , Humanos , Arginina/metabolismo , Transporte Biológico , Dipéptidos/metabolismo , Células HEK293 , Lisina/metabolismo , Lisosomas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Fosfoproteínas/metabolismo
2.
Life Sci Alliance ; 4(6)2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33758075

RESUMEN

Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter's major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Ácido Cítrico/metabolismo , Neoplasias Pancreáticas/metabolismo , Fibroblastos Asociados al Cáncer/fisiología , Línea Celular Tumoral , Epigénesis Genética , Humanos , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Neoplasias Pancreáticas/patología , Células del Estroma/metabolismo , Microambiente Tumoral/fisiología , Neoplasias Pancreáticas
3.
Cancer Res ; 78(10): 2513-2523, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29510993

RESUMEN

Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.Significance: Uptake of extracellular citrate through pmCiC can be blocked with gluconate to reduce tumor growth and to alter metabolic characteristics of tumor tissue. Cancer Res; 78(10); 2513-23. ©2018 AACR.


Asunto(s)
Proteínas de Transporte de Anión/antagonistas & inhibidores , Proteínas de Transporte de Anión/metabolismo , Proliferación Celular/efectos de los fármacos , Ácido Cítrico/metabolismo , Gluconatos/farmacología , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias de la Próstata/patología , Animales , Línea Celular Tumoral , Células Epiteliales/metabolismo , Ácidos Grasos/biosíntesis , Glucólisis/fisiología , Humanos , Masculino , Ratones , Transportadores de Anión Orgánico , Próstata/citología , Próstata/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética
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