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1.
Nature ; 616(7956): 339-347, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36991126

RESUMO

There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.


Assuntos
Ornitina-Oxo-Ácido Transaminase , Neoplasias Pancreáticas , Poliaminas , Animais , Humanos , Camundongos , Arginina/deficiência , Arginina/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Ornitina/biossíntese , Ornitina/metabolismo , Ornitina-Oxo-Ácido Transaminase/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poliaminas/metabolismo , Microambiente Tumoral
2.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33653947

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Glutamato-Amônia Ligase/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Estabilidade Enzimática , Glutamato-Amônia Ligase/genética , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética
3.
Cancer Res ; 80(6): 1357-1367, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31969373

RESUMO

Ovarian cancer has few known risk factors, hampering identification of high-risk women. We assessed the association of prediagnostic plasma metabolites (N = 420) with risk of epithelial ovarian cancer, including both borderline and invasive tumors. A total of 252 cases and 252 matched controls from the Nurses' Health Studies were included. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI), comparing the 90th-10th percentile in metabolite levels, using the permutation-based Westfall and Young approach to account for testing multiple correlated hypotheses. Weighted gene coexpression network analysis (WGCNA; n = 10 metabolite modules) and metabolite set enrichment analysis (n = 23 metabolite classes) were also evaluated. An increase in pseudouridine levels from the 10th to the 90th percentile was associated with a 2.5-fold increased risk of overall ovarian cancer (OR = 2.56; 95% CI, 1.48-4.45; P = 0.001/adjusted P = 0.15); a similar risk estimate was observed for serous/poorly differentiated tumors (n = 176 cases; comparable OR = 2.38; 95% CI, 1.33-4.32; P = 0.004/adjusted P = 0.55). For nonserous tumors (n = 34 cases), pseudouridine and C36:2 phosphatidylcholine plasmalogen had the strongest statistical associations (OR = 9.84; 95% CI, 2.89-37.82; P < 0.001/adjusted P = 0.07; and OR = 0.11; 95% CI, 0.03-0.35; P < 0.001/adjusted P = 0.06, respectively). Five WGCNA modules and 9 classes were associated with risk overall at FDR ≤ 0.20. Triacylglycerols (TAG) showed heterogeneity by tumor aggressiveness (case-only heterogeneity P < 0.0001). The TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. In summary, this study suggests that pseudouridine may be a novel risk factor for ovarian cancer and that TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. SIGNIFICANCE: Pseudouridine represents a potential novel risk factor for ovarian cancer and triglycerides may be important particularly in rapidly fatal ovarian tumors.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Epitelial do Ovário/epidemiologia , Neoplasias Ovarianas/epidemiologia , Pseudouridina/sangue , Triglicerídeos/sangue , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Metabolômica , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo , Estudos Prospectivos , Pseudouridina/metabolismo , Medição de Risco/métodos , Fatores de Risco , Triglicerídeos/metabolismo
4.
Proc Natl Acad Sci U S A ; 115(16): 4228-4233, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29610318

RESUMO

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (Irs1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with Irs1/Irs2 loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for KRAS-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in KRAS-mutant NSCLC.


Assuntos
Carcinogênese/metabolismo , Carcinoma Pulmonar de Células não Pequenas/prevenção & controle , Genes ras , Proteínas Substratos do Receptor de Insulina/fisiologia , Fator de Crescimento Insulin-Like I/fisiologia , Insulina/farmacologia , Neoplasias Pulmonares/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Células A549 , Aminoácidos/metabolismo , Animais , Autofagia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Códon de Terminação , Humanos , Proteínas Substratos do Receptor de Insulina/deficiência , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatologia , Camundongos , Proteínas de Neoplasias/fisiologia , Proteólise , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/fisiologia
5.
Nat Commun ; 8(1): 242, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28808255

RESUMO

Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer.Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity-driven PDA tumor growth.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Mucoproteínas/metabolismo , Obesidade/complicações , Neoplasias Pancreáticas/enzimologia , Proteínas/metabolismo , Animais , Arginina/metabolismo , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Mucoproteínas/genética , Proteínas Oncogênicas , Ornitina/metabolismo , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas/genética
6.
Nat Commun ; 8: 13989, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28071763

RESUMO

Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize ß4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell ß4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition.


Assuntos
Células Epiteliais/fisiologia , Matriz Extracelular/metabolismo , Integrina beta4/metabolismo , Laminina/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/fisiologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Feminino , Fibroblastos/metabolismo , Humanos , Integrina beta4/genética , Laminina/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos , Fosfatidilinositol 3-Quinases/metabolismo , Inanição
7.
J Am Chem Soc ; 135(37): 13927-33, 2013 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-23968233

RESUMO

A substantial challenge for genomic enzymology is the reliable annotation for proteins of unknown function. Described here is an interrogation of uncharacterized enzymes from the amidohydrolase superfamily using a structure-guided approach that integrates bioinformatics, computational biology, and molecular enzymology. Previously, Tm0936 from Thermotoga maritima was shown to catalyze the deamination of S-adenosylhomocysteine (SAH) to S-inosylhomocysteine (SIH). Homologues of Tm0936 homologues were identified, and substrate profiles were proposed by docking metabolites to modeled enzyme structures. These enzymes were predicted to deaminate analogues of adenosine including SAH, 5'-methylthioadenosine (MTA), adenosine (Ado), and 5'-deoxyadenosine (5'-dAdo). Fifteen of these proteins were purified to homogeneity, and the three-dimensional structures of three proteins were determined by X-ray diffraction methods. Enzyme assays supported the structure-based predictions and identified subgroups of enzymes with the capacity to deaminate various combinations of the adenosine analogues, including the first enzyme (Dvu1825) capable of deaminating 5'-dAdo. One subgroup of proteins, exemplified by Moth1224 from Moorella thermoacetica, deaminates guanine to xanthine, and another subgroup, exemplified by Avi5431 from Agrobacterium vitis S4, deaminates two oxidatively damaged forms of adenine: 2-oxoadenine and 8-oxoadenine. The sequence and structural basis of the observed substrate specificities were proposed, and the substrate profiles for 834 protein sequences were provisionally annotated. The results highlight the power of a multidisciplinary approach for annotating enzymes of unknown function.


Assuntos
Nucleosídeo Desaminases/química , Domínio Catalítico , Cristalografia por Raios X , Ensaios Enzimáticos , Cinética , Modelos Moleculares , Estrutura Molecular , Nucleosídeo Desaminases/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato
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