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J Exp Med ; 217(3)2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31961917


Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism.

Nat Commun ; 10(1): 201, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30643150


Under hypoxia, most of glucose is converted to secretory lactate, which leads to the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid over-accumulating ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate, which is indispensable to glutamine-carbon metabolism under hypoxia. We found that glutamine nitrogen is necessary to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. Furthermore, we found that the specific metabolic pathway occurs in vivo and is required for tumor growth. The identified metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Therefore, our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.

Glutamina/metabolismo , Redes e Vias Metabólicas , Metaboloma , Neoplasias/metabolismo , Ácido Orótico/análogos & derivados , Acetilcoenzima A/metabolismo , Amônia/metabolismo , Amônia/toxicidade , Animais , Carbono/química , Carbono/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Glucose/metabolismo , Glutamina/química , Células HEK293 , Humanos , Ácido Láctico/metabolismo , Lipogênese , Metabolômica , Camundongos , Camundongos Nus , Neoplasias/sangue , Neoplasias/mortalidade , Neoplasias/patologia , Nitrogênio/química , Nitrogênio/metabolismo , Nucleotídeos/biossíntese , Ácido Orótico/metabolismo , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
OMICS ; 21(5): 266-274, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28481732


Colon cancer patients have major unmet needs in terms of robust diagnostics and molecular biomarkers for personalized therapeutics. We have previously reported that human CAP10-like protein 46 kDa (hCLP46) is overexpressed in human acute myelogenous leukemia, T acute lymphoblastic leukemia, and leukemia cell lines. We extend this line of biomarker and diagnostic discovery research by investigating hCLP46 expression in colorectal cancer (CRC) tissues and examine the possibility of hCLP46 as a candidate biomarker for diagnosis and prognosis of CRC. Using a tissue microarray analysis approach, we found that hCLP46 is (1) overexpressed in 90 CRC tissues compared with 90 matched noncancerous tissues and (2) positively correlated with higher tumor-node-metastasis (TNM) stage, lymph node metastasis, and shorter survival time. Moreover, in vitro experiments demonstrated that downregulation of hCLP46 in CRC cells results in proliferation arrest and adhesion enhancement, while apoptosis is unchanged. Further transcriptome profile analysis corroborated that the adhesion pathway is related to hCLP46 downregulation. This report for the first time, to the best of our knowledge, demonstrates that hCLP46 promotes tumor malignancy in CRC cells. We suggest that hCLP46 is warranted for further research as a candidate biomarker for clinical phenotypes related to colon cancer.

Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Glucosiltransferases/metabolismo , Adulto , Biomarcadores Tumorais/genética , Células CACO-2 , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glucosiltransferases/genética , Células HCT116 , Humanos , Linfonodos/patologia , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Medicina de Precisão , Prognóstico
Biochem Biophys Res Commun ; 408(1): 84-8, 2011 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-21458412


Human CAP10-like protein 46 kDa (hCLP46) is the homolog of Rumi, which is the first identified protein O-glucosyltransferase that modifies Notch receptor in Drosophila. Dysregulation of hCLP46 occurs in many hematologic diseases, but the role of hCLP46 remains unclear. Knockdown of hCLP46 by RNA interference resulted in decreased protein levels of endogenous Notch1, Notch intracellular domain (NICD) and Notch target gene Hes-1, suggesting the impairment of the Notch signaling. However, neither cell surface Notch expression nor ligand binding activities were affected. In addition, down-regulated expression of hCLP46 inhibited the proliferation of U937 cells, which was correlated with increased cyclin-dependent kinase inhibitor (CDKI) CDKN1B (p27) and decreased phosphorylation of retinoblastoma (RB) protein. We showed that lack of hCLP46 results in impaired ligand induced Notch activation in mammalian cell, and hCLP46 regulates the proliferation of U937 cell through CDKI-RB signaling pathway, which may be important for the pathogenesis of leukemia.

Proliferação de Células , Proteínas/fisiologia , Receptores Notch/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína Quinase CDC2/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Técnicas de Silenciamento de Genes , Glucosiltransferases , Proteínas de Homeodomínio/metabolismo , Humanos , Células Jurkat , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Proteínas/genética , Interferência de RNA , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptores Notch/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Fatores de Transcrição HES-1 , Células U937
Genet Test Mol Biomarkers ; 14(1): 127-33, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20143914


AIMS: We earlier identified a novel gene human CAP10-like protein 46 KD (hCLP46) from human acute myelogenous leukemia (AML) transformed from myelodysplastic syndrome CD34(+) cells, but the function of this gene remains unclear. In this study, a real-time polymerase chain reaction-based assay was developed to quantify expression of hCLP46 in the peripheral blood of AML and T-acute lymphoblastic leukemia (T-ALL) primary samples and in six leukemic cell lines. Also, we investigated expression of CDKN2A/B and the apoptosis in U937 cells when hCLP46 is downregulated in vitro. RESULTS: Our findings showed that hCLP46 was overexpressed in AML, T-ALL, and the leukemic cell lines. Suppressing hCLP46 overexpression had no effect on expression of CDKN2A/B and apoptosis of U937 cells. CONCLUSION: Considering that hCLP46 has the capability of modifying the Notch pathway, our finding adds weight to the importance of Notch signaling in hematopoiesis and suggests that overexpression of hCLP46 might be an early event in the pathogenesis of AML and T-ALL.

Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas/genética , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA/genética , Expressão Gênica , Genes p16 , Glucosiltransferases , Hematopoese/genética , Hematopoese/fisiologia , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/fisiopatologia , Proteínas/antagonistas & inibidores , RNA Interferente Pequeno/genética , Receptores Notch/fisiologia , Transdução de Sinais , Transfecção , Células U937
J Hum Genet ; 54(8): 457-60, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19590515


Normal function of the dopaminergic system is necessary for speech fluency. There was evidence that the activities of dopamine transporter (DAT) and dopamine D2 receptor (DRD2) could be altered in people with speech disfluency. This study aims to ascertain the possible correlation between two dopaminergic genes (SLC6A3 and DRD2) and disorder of speech fluency, and to determine the allelic frequencies of the five single-nucleotide polymorphisms (SNPs) (rs2617604, rs28364997, rs28364998 in SLC6A3 and rs6275, rs6277 in DRD2) among Han Chinese patients with this disorder. A sample of 112 patients with speech disfluency and 112 gender-matched controls were included in this case-control study. The results show that the presence of C allele at rs6277 in DRD2 gene is associated with increased susceptibility to the disorder, whereas T allele is protective. Haplotype 939T/957T is also a protective factor.

Grupo com Ancestrais do Continente Asiático/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Dopamina D2/genética , Gagueira/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Masculino , Reação em Cadeia da Polimerase , Adulto Jovem