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1.
Nat Commun ; 10(1): 96, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626880

RESUMO

Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Esqualeno Mono-Oxigenase/antagonistas & inibidores , Esqualeno Mono-Oxigenase/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Colesterol/biossíntese , Deleção de Genes , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos
2.
Cell Rep ; 17(3): 876-890, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27732861

RESUMO

Although aberrant metabolism in tumors has been well described, the identification of cancer subsets with particular metabolic vulnerabilities has remained challenging. Here, we conducted an siRNA screen focusing on enzymes involved in the tricarboxylic acid (TCA) cycle and uncovered a striking range of cancer cell dependencies on OGDH, the E1 subunit of the alpha-ketoglutarate dehydrogenase complex. Using an integrative metabolomics approach, we identified differential aspartate utilization, via the malate-aspartate shuttle, as a predictor of whether OGDH is required for proliferation in 3D culture assays and for the growth of xenograft tumors. These findings highlight an anaplerotic role of aspartate and, more broadly, suggest that differential nutrient utilization patterns can identify subsets of cancers with distinct metabolic dependencies for potential pharmacological intervention.


Assuntos
Ácido Aspártico/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Neoplasias/metabolismo , Animais , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Humanos , RNA Interferente Pequeno/metabolismo
3.
Cancer Cell ; 24(2): 213-228, 2013 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-23911236

RESUMO

Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis.


Assuntos
Neoplasias da Mama/enzimologia , Hexoquinase/metabolismo , Neoplasias Pulmonares/enzimologia , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glicólise , Hexoquinase/biossíntese , Hexoquinase/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Knockout , Transplante Heterólogo
4.
Cell ; 142(3): 456-67, 2010 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-20691904

RESUMO

RNA import into mammalian mitochondria is considered essential for replication, transcription, and translation of the mitochondrial genome but the pathway(s) and factors that control this import are poorly understood. Previously, we localized polynucleotide phosphorylase (PNPASE), a 3' --> 5' exoribonuclease and poly-A polymerase, in the mitochondrial intermembrane space, a location lacking resident RNAs. Here, we show a new role for PNPASE in regulating the import of nuclear-encoded RNAs into the mitochondrial matrix. PNPASE reduction impaired mitochondrial RNA processing and polycistronic transcripts accumulated. Augmented import of RNase P, 5S rRNA, and MRP RNAs depended on PNPASE expression and PNPASE-imported RNA interactions were identified. PNPASE RNA processing and import activities were separable and a mitochondrial RNA targeting signal was isolated that enabled RNA import in a PNPASE-dependent manner. Combined, these data strongly support an unanticipated role for PNPASE in mediating the translocation of RNAs into mitochondria.


Assuntos
Mitocôndrias/metabolismo , Polirribonucleotídeo Nucleotidiltransferase/metabolismo , RNA/metabolismo , Animais , Linhagem Celular , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Polirribonucleotídeo Nucleotidiltransferase/genética , Processamento Pós-Transcricional do RNA , Ribonuclease P/metabolismo , Saccharomyces cerevisiae/metabolismo
5.
Blood ; 113(11): 2478-87, 2009 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-19147787

RESUMO

B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B- and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg B-cell tumors to discover tumor-associated epigenetic changes, and identified hypermethylation of sprouty2 (Spry2). Sprouty proteins are context-dependent negative or positive regulators of MAPK-ERK pathway signaling, but their role(s) in B-cell physiology or pathology are unknown. Here we show that repression of Spry2 expression in TCL1-tg mouse and human B-cell lymphomas and cell lines is associated with dense DNA hypermethylation and was reversed by inhibition of DNA methylation. Spry2 expression was induced in normal splenic B cells by CD40/B-cell receptor costimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability. Conversely, loss of Spry2 function hyperactivated MAPK-ERK signaling and caused increased B-cell proliferation. Combined, these results implicate epigenetic silencing of Spry2 expression in B lymphoma progression and suggest it as a companion lesion to ectopic TCL1 expression in enhancing MAPK-ERK pathway signaling.


Assuntos
Linfócitos B/fisiologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Proteínas de Membrana/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Linfócitos B/metabolismo , Antígenos CD40/metabolismo , Antígenos CD40/fisiologia , Metilação de DNA/fisiologia , Feminino , Inativação Gênica/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases , Células Tumorais Cultivadas
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