Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Sci Immunol ; 6(64): eabg7836, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34597124

RESUMO

"Stem-like" TCF1+ CD8+ T (TSL) cells are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy, but, as tumors contain signals that should drive T cell terminal differentiation, how these cells are maintained in tumors remains unclear. In this study, we found that a small number of TCF1+ tumor-specific CD8+ T cells were present in lung tumors throughout their development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from "hot" (T cell inflamed) to "cold" (non­T cell inflamed). By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic lymphocytic choriomeningitis virus infection, and this population was stable over time despite the changes in the TME. dLN T cells were the developmental precursors of, and were clonally related to, their more differentiated intratumoral counterparts. Our data support the hypothesis that dLN T cells are the developmental precursors of the TCF1+ T cells in tumors that are maintained by continuous migration. Last, CD8+ T cells similar to TSL were also present in LNs from patients with lung adenocarcinoma, suggesting that a similar model may be relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function in sustaining antitumor T cells during tumor development and in protecting them from the terminal differentiation that occurs in the TME.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias Pulmonares/imunologia , Linfonodos/imunologia , Animais , Feminino , Imunoterapia , Neoplasias Pulmonares/terapia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microambiente Tumoral/imunologia
2.
Cell Metab ; 29(2): 285-302.e7, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30415923

RESUMO

AMPK, a conserved sensor of low cellular energy, can either repress or promote tumor growth depending on the context. However, no studies have examined AMPK function in autochthonous genetic mouse models of epithelial cancer. Here, we examine the role of AMPK in murine KrasG12D-mediated non-small-cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor-the predominant upstream activating kinase of AMPK and 12 related kinases. Unlike LKB1 deletion, AMPK deletion in KrasG12D lung tumors did not accelerate lung tumor growth. Moreover, deletion of AMPK in KrasG12D p53f/f tumors reduced lung tumor burden. We identified a critical role for AMPK in regulating lysosomal gene expression through the Tfe3 transcription factor, which was required to support NSCLC growth. Thus, AMPK supports the growth of KrasG12D-dependent lung cancer through the induction of lysosomes, highlighting an unrecognized liability of NSCLC.


Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Linhagem Celular Tumoral , Mutação com Perda de Função , Camundongos
3.
Cancer Discov ; 9(11): 1606-1627, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31350328

RESUMO

Mutations in the LKB1 (also known as STK11) tumor suppressor are the third most frequent genetic alteration in non-small cell lung cancer (NSCLC). LKB1 encodes a serine/threonine kinase that directly phosphorylates and activates 14 AMPK family kinases ("AMPKRs"). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Here, we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing a surprising critical role for the SIK subfamily. Conditional genetic loss of Sik1 revealed increased tumor growth in mouse models of Kras-dependent lung cancer, which was further enhanced by loss of the related kinase Sik3. As most known substrates of the SIKs control transcription, gene-expression analysis was performed, revealing upregulation of AP1 and IL6 signaling in common between LKB1- and SIK1/3-deficient tumors. The SIK substrate CRTC2 was required for this effect, as well as for proliferation benefits from SIK loss. SIGNIFICANCE: The tumor suppressor LKB1/STK11 encodes a serine/threonine kinase frequently inactivated in NSCLC. LKB1 activates 14 downstream kinases in the AMPK family controlling growth and metabolism, although which kinases are critical for LKB1 tumor-suppressor function has remained an enigma. Here we unexpectedly found that two understudied kinases, SIK1 and SIK3, are critical targets in lung cancer.This article is highlighted in the In This Issue feature, p. 1469.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP , Animais , Sistemas CRISPR-Cas , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Edição de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Transplante de Neoplasias , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Carga Tumoral
4.
Nat Med ; 22(10): 1108-1119, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27643638

RESUMO

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/biossíntese , Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Pirimidinonas/farmacologia , Tiofenos/farmacologia , Proteínas Quinases Ativadas por AMP , Acetiltransferases/antagonistas & inibidores , Regulação Alostérica , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Humanos , Metabolismo dos Lipídeos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Aging Cell ; 13(5): 911-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25059582

RESUMO

Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR), robustly extends the lifespan of model organisms including mice. We recently found that chronic treatment with rapamycin not only inhibits mTOR complex 1 (mTORC1), the canonical target of rapamycin, but also inhibits mTOR complex 2 (mTORC2) in vivo. While genetic evidence strongly suggests that inhibition of mTORC1 is sufficient to promote longevity, the impact of mTORC2 inhibition on mammalian longevity has not been assessed. RICTOR is a protein component of mTORC2 that is essential for its activity. We examined three different mouse models of Rictor loss: mice heterozygous for Rictor, mice lacking hepatic Rictor, and mice in which Rictor was inducibly deleted throughout the body in adult animals. Surprisingly, we find that depletion of RICTOR significantly decreases male, but not female, lifespan. While the mechanism by which RICTOR loss impairs male survival remains obscure, we find that the effect of RICTOR depletion on lifespan is independent of the role of hepatic mTORC2 in promoting glucose tolerance. Our results suggest that inhibition of mTORC2 signaling is detrimental to males, which may explain in part why interventions that decrease mTOR signaling show greater efficacy in females.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Longevidade/fisiologia , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Feminino , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Proteína Companheira de mTOR Insensível à Rapamicina , Fatores Sexuais , Transdução de Sinais
6.
Nat Genet ; 45(1): 104-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23202129

RESUMO

There is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anticancer therapy are under way. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, SLC16A1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Furthermore, forced MCT1 expression in 3-BrPA-resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors.


Assuntos
Transportadores de Ácidos Monocarboxílicos/genética , Piruvatos/metabolismo , Simportadores/genética , Animais , Transporte Biológico/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Camundongos , Camundongos Nus , Transportadores de Ácidos Monocarboxílicos/metabolismo , Piruvatos/farmacologia , Simportadores/metabolismo
7.
J Biol Chem ; 278(18): 15727-34, 2003 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-12595525

RESUMO

The coactivator function of cAMP-responsive element-binding protein (CREB)-binding protein (CBP) is partly caused by its histone acetyltransferase activity. However, it has become increasingly clear that CBP acetylates both histones and non-histone proteins, many of which are transcription factors. Here we investigate the role of CBP acetylase activity in CREB-mediated gene expression. We show that CREB is acetylated within the cell and that in vitro, CREB is acetylated by CBP, but not by another acetylase, p300/CBP-associated factor. The acetylation sites within CREB were mapped to three lysines within the CREB activation domain. Although inhibition of histone deacetylase activity results in an increase of CREB- or CBP-mediated gene expression, mutation of all three putative acetylation sites in the CREB activation domain markedly enhances the ability of CREB to activate a cAMP-responsive element-dependent reporter gene. Furthermore, these CREB lysine mutations do not increase interaction with the CRE or CBP. These data suggest that the transactivation potential of CREB may be modulated through acetylation by CBP. We propose that in addition to its functions as a bridging molecule and histone acetyltransferase, the ability of CBP to acetylate CREB may play a key role in modulating CREB-mediated gene expression.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Nucleares/fisiologia , Transativadores/fisiologia , Ativação Transcricional , Acetilação , Sequência de Aminoácidos , Animais , Células COS , Proteína de Ligação a CREB , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/química , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Regulação da Expressão Gênica , Dados de Sequência Molecular , Fosforilação , Transfecção
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA