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1.
Cell ; 141(1): 166-77, 2010 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-20371352

RESUMO

It has been recently reported that treatment with an anti-placenta growth factor (PlGF) antibody inhibits metastasis and primary tumor growth. Here we show that, although anti-PlGF treatment inhibited wound healing, extravasation of B16F10 cells, and growth of a tumor engineered to overexpress the PlGF receptor (VEGFR-1), neutralization of PlGF using four novel blocking antibodies had no significant effect on tumor angiogenesis in 15 models. Also, genetic ablation of the tyrosine kinase domain of VEGFR-1 in the host did not result in growth inhibition of the anti-VEGF-A sensitive or resistant tumors tested. Furthermore, combination of anti-PlGF with anti-VEGF-A antibodies did not result in greater antitumor efficacy than anti-VEGF-A monotherapy. In conclusion, our data argue against an important role of PlGF during primary tumor growth in most models and suggest that clinical evaluation of anti-PlGF antibodies may be challenging.


Assuntos
Neoplasias/irrigação sanguínea , Neovascularização Patológica , Proteínas da Gravidez/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fator de Crescimento Placentário , Proteínas da Gravidez/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular
2.
Nat Immunol ; 9(5): 513-21, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18391955

RESUMO

Phosphatidylinositol-3-OH kinase (PI(3)K) and the nutrient sensor mTOR are evolutionarily conserved regulators of cell metabolism. Here we show that PI(3)K and mTOR determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. The key lymph node-homing receptors CD62L (L-selectin) and CCR7 were highly expressed on naive T lymphocytes but were downregulated after immune activation. CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription. The p110delta subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110delta was mediated by mTOR through regulation of the transcription factor KLF2. PI(3)K-mTOR nutrient-sensing pathways also determined expression of the chemokine receptor CCR7 and regulated lymphocyte trafficking in vivo. Hence, lymphocytes use PI(3)K and mTOR to match metabolism and trafficking.


Assuntos
Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Quinases/fisiologia , Linfócitos T/imunologia , Animais , Movimento Celular , Selectina L/metabolismo , Linfonodos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores CCR7/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR
3.
Nature ; 464(7291): 1052-7, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20393564

RESUMO

The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.


Assuntos
Anticorpos/farmacologia , Anticorpos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores Notch/antagonistas & inibidores , Inibidores da Angiogênese/imunologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos/efeitos adversos , Anticorpos/imunologia , Especificidade de Anticorpos/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Biblioteca de Peptídeos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/imunologia , Receptor Notch2/antagonistas & inibidores , Receptor Notch2/imunologia , Receptores Notch/genética , Receptores Notch/imunologia , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Proc Natl Acad Sci U S A ; 107(50): 21248-55, 2010 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-21081700

RESUMO

Priming of the organ-specific premetastatic sites is thought to be an important yet incompletely understood step during metastasis. In this study, we show that the metastatic tumors we examined overexpress granulocyte-colony stimulating factor (G-CSF), which expands and mobilizes Ly6G+Ly6C+ granulocytes and facilitates their subsequent homing at distant organs even before the arrival of tumor cells. Moreover, G-CSF-mobilized Ly6G+Ly6C+ cells produce the Bv8 protein, which has been implicated in angiogenesis and mobilization of myeloid cells. Anti-G-CSF or anti-Bv8 antibodies significantly reduced lung metastasis. Transplantation of Bv8 null fetal liver cells into lethally irradiated hosts also reduced metastasis. We identified an unexpected role for Bv8: the ability to stimulate tumor cell migration through activation of one of the Bv8 receptors, prokineticin receptor (PKR)-1. Finally, we show that administration of recombinant G-CSF is sufficient to increase the numbers of Ly6G+Ly6C+ cells in organ-specific metastatic sites and results in enhanced metastatic ability of several tumors.


Assuntos
Antígenos Ly/imunologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Perfilação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/genética , Granulócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos SCID , Análise em Microsséries , Transplante de Neoplasias , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia
5.
Nat Cancer ; 4(6): 812-828, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37277530

RESUMO

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Medicina de Precisão , Fatores de Transcrição/metabolismo , Transdução de Sinais
6.
Cancer Discov ; 11(3): 778-793, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33208393

RESUMO

Hippo pathway dysregulation occurs in multiple cancers through genetic and nongenetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defining tumors that are Hippo pathway-dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type-agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies. SIGNIFICANCE: An integrated chemicogenomics strategy was developed to identify a lineage-independent signature for the Hippo pathway in cancers. Evaluating transcriptional profiles using a machine-learning method led to identification of a relationship between YAP/TAZ dependency and MAPK pathway activity. The results help to nominate potential combination therapies with Hippo pathway inhibition.This article is highlighted in the In This Issue feature, p. 521.


Assuntos
Quimioinformática/métodos , Biologia Computacional/métodos , Genômica/métodos , Via de Sinalização Hippo , Sistema de Sinalização das MAP Quinases , Aprendizado de Máquina , Transdução de Sinais , Humanos
7.
J Exp Med ; 200(7): 883-94, 2004 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-15452180

RESUMO

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates cell survival and proliferation mediated by phosphoinositol 3 kinases. We have explored the role of the phosphoinositol(3,4,5)P3-phosphatase PTEN in T cell development by analyzing mice with a T cell-specific deletion of PTEN. Pten(flox/flox)Lck-Cre mice developed thymic lymphomas, but before the onset of tumors, they showed normal thymic cellularity. To reveal a regulatory role of PTEN in proliferation of developing T cells we have crossed PTEN-deficient mice with mice deficient for interleukin (IL)-7 receptor and pre-T cell receptor (TCR) signaling. Analysis of mice deficient for Pten and CD3gamma; Pten and gammac; or Pten, gammac, and Rag2 revealed that deletion of PTEN can substitute for both IL-7 and pre-TCR signals. These double- and triple-deficient mice all develop normal levels of CD4CD8 double negative and double positive thymocytes. These data indicate that PTEN is an important regulator of proliferation of developing T cells in the thymus.


Assuntos
Proteínas Tirosina Fosfatases/metabolismo , Transdução de Sinais/fisiologia , Linfócitos T/fisiologia , Timo/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proliferação de Células , Sobrevivência Celular/fisiologia , Primers do DNA , Citometria de Fluxo , Genótipo , Immunoblotting , Imunoprecipitação , Interleucina-7/metabolismo , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase , Reação em Cadeia da Polimerase , Proteínas Tirosina Fosfatases/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Timo/fisiologia , Proteínas Supressoras de Tumor/fisiologia
8.
Cancer Res ; 80(8): 1656-1668, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31988076

RESUMO

The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that pancreatic intraepithelial neoplasia driven by oncogenic mutant KrasG12D progressed to pancreatic adenocarcinoma in the absence of BAP1. The Hippo pathway was deregulated in BAP1-deficient pancreatic tumors, with the tumor suppressor LATS exhibiting enhanced ubiquitin-dependent proteasomal degradation. Therefore, BAP1 may limit tumor progression by stabilizing LATS and thereby promoting activity of the Hippo tumor suppressor pathway. SIGNIFICANCE: BAP1 is mutated in a broad spectrum of tumors. Pancreatic Bap1 deficiency causes acinar atrophy but combines with oncogenic Ras to produce pancreatic tumors. BAP1-deficient tumors exhibit deregulation of the Hippo pathway.See related commentary by Brekken, p. 1624.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Via de Sinalização Hippo , Humanos , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase
9.
Sci Immunol ; 3(22)2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29678836

RESUMO

Loss of function of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) is associated with a wide spectrum of cancers. We report that tamoxifen-induced BAP1 deletion in adult mice resulted in severe thymic atrophy. BAP1 was critical for T cell development at several stages. In the thymus, BAP1 was required for progression through the pre-T cell receptor checkpoint. Peripheral T cells lacking BAP1 demonstrated a defect in homeostatic and antigen-driven expansion. Deletion of BAP1 resulted in suppression of E2F target genes and defects in cell cycle progression, which was dependent on the catalytic activity of BAP1, but did not require its interaction with host cell factor-1 (HCF-1). Loss of BAP1 led to increased monoubiquitination of histone H2A at Lys119 (H2AK119ub) throughout the T cell lineage, in particular in immature thymocytes, but did not alter trimethylation of histone H3 at Lys27 (H3K27me3). Deletion of BAP1 also abrogated B cell development in the bone marrow. Our findings uncover a nonredundant function for BAP1 in maintaining the lymphoid lineage.


Assuntos
Linfócitos T/metabolismo , Timócitos/metabolismo , Timo/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Animais , Atrofia , Ciclo Celular/genética , Perfilação da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Lisina/genética , Lisina/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Timo/patologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação
10.
Sci Signal ; 11(547)2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206136

RESUMO

The Hippo signaling pathway regulates organ size and plays critical roles in maintaining tissue growth, homeostasis, and regeneration. Dysregulated in a wide spectrum of cancers, in mammals, this pathway is regulated by two key effectors, YAP and TAZ, that may functionally overlap. We found that TAZ promoted liver inflammation and tumor development. The expression of TAZ, but not YAP, in human liver tumors positively correlated with the expression of proinflammatory cytokines. Hyperactivated TAZ induced substantial myeloid cell infiltration into the liver and the secretion of proinflammatory cytokines through a TEAD-dependent mechanism. Furthermore, tumors with hyperactivated YAP and TAZ had distinct transcriptional signatures, which included the increased expression of inflammatory cytokines in TAZ-driven tumors. Our study elucidated a previously uncharacterized link between TAZ activity and inflammatory responses that influence tumor development in the liver.


Assuntos
Proteínas de Ligação a DNA/genética , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/genética , Fígado/metabolismo , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular , Citocinas/genética , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica/métodos , Via de Sinalização Hippo , Humanos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Mutação , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição de Domínio TEA , Transativadores , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Transplante Heterólogo
11.
Cancer Res ; 77(6): 1439-1452, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108512

RESUMO

Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc, and the mammary stem cell regulator Id4 This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers. Cancer Res; 77(6); 1439-52. ©2017 AACR.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Neoplasia de Células Basais/patologia , Receptor Notch3/metabolismo , Animais , Apoptose , Neoplasias da Mama/metabolismo , Feminino , Humanos , Camundongos , Camundongos Knockout , Camundongos SCID , Neoplasia de Células Basais/metabolismo , Receptor Notch3/genética , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Lett ; 346(2): 237-48, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24384093

RESUMO

T cell acute lymphoblastic leukemias (T-ALLs) commonly display constitutively active PI3K/mTOR and Notch signaling. However, controversy surrounds whether these pathways have independent functions and whether Pten loss is sufficient to generate resistance to Notch inhibition. Here we report that Pten(-/-) T-ALL is sensitive to either PI3K/mTOR or Notch inhibition alone, each pathway controlling distinct downstream signaling events that cannot be rescued by activation of the other pathway, consistent with independent, non-redundant functions. Although many human T-ALLs display constitutively activating Notch1 mutations, primary Pten(-/-) T-ALLs expressed wild-type Notch1 and depended on the Notch ligand DLL4 in vivo. Pten(-/-) T-ALLs with or without γc/TCR signaling responded similarly to PI3K/mTOR and Notch inhibition, although extended culture in vitro occasionally induced Notch-independent growth. However, unlike the T-ALLs lacking only Pten, eight of 23 Pten(-/-) T-ALLs that also lacked γc/TCR signaling accumulated Notch1 mutations, suggesting crosstalk between γc/TCR and Notch signaling. Importantly, we concluded that loss of γc/TCR signaling also inhibited thymic exit of Pten(-/-) T-ALLs. Our results may be clinically relevant in revealing that Pten loss is not sufficient to engender resistance to Notch inhibition, uncovering a role in T-ALL for ligand-dependent induction of wild-type Notch1, and suggesting that γc/TCR signaling could be targeted for preventing metastasis.


Assuntos
PTEN Fosfo-Hidrolase/deficiência , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Timo/metabolismo , Timo/patologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Ligação ao Cálcio , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
13.
Cancer Lett ; 336(1): 114-26, 2013 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-23612073

RESUMO

We show here that the antidiabetic agents metformin and phenformin and the AMPK activator AICAR exert strong anti-tumoural effects on tPTEN-/- lymphoma cells and on human T-ALL cell lines and primary samples. The compounds act by inhibiting tumour metabolism and proliferation and by inducing apoptosis in parallel with an activation of AMPK and an inhibition of constitutive mTOR. In tPTEN-/- cells, the drugs potentiated the anti-leukaemic effects of dexamethasone, and metformin and phenformin synergised with 2-deoxyglucose (2DG) to impair tumour cell survival. In vivo, metformin and AICAR strongly decreased the growth of luciferase-expressing tPTEN-/- cells xenografted in Nude mice, demonstrating that metabolism targeting could be a potent adjuvant strategy for lymphoma/leukaemia treatment.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Regulação Neoplásica da Expressão Gênica , Linfoma de Células T/metabolismo , Metformina/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Fenformin/farmacologia , Ribonucleotídeos/farmacologia , Alelos , Aminoimidazol Carboxamida/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Ativação Enzimática , Humanos , Células Jurkat , Camundongos , Camundongos Nus , Transplante de Neoplasias , Transgenes
14.
Cancer Lett ; 333(1): 76-88, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23348702

RESUMO

The membrane-bound carbonic anhydrase isoforms CAIX and CAXII, underpin a pH-regulating system that enables hypoxic tumor cell survival. Here, we observed for the first time an upregulation of CAXII in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LL) cells. First we showed that CAXII is overexpressed in thymocytes from tPTEN-/- mice suffering of T lymphoma and that its pharmacological inhibition decreased cell proliferation and induced apoptosis. The same results were observed with the SupT1 human T cell lymphoma line. In addition we observed an upregulation of CAXII in human T-ALL samples supporting the case that CAXII may represent a new therapeutic target for T-ALL/LL.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/fisiologia , Proliferação de Células/efeitos dos fármacos , Linfoma de Células T/tratamento farmacológico , Animais , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/genética , Linhagem Celular Tumoral , Humanos , Concentração de Íons de Hidrogênio , Linfoma de Células T/enzimologia , Camundongos , PTEN Fosfo-Hidrolase/fisiologia
15.
J Exp Med ; 206(11): 2441-54, 2009 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-19808258

RESUMO

In normal T cell progenitors, phosphoinositide-dependent kinase l (PDK1)-mediated phosphorylation and activation of protein kinase B (PKB) is essential for the phosphorylation and inactivation of Foxo family transcription factors, and also controls T cell growth and proliferation. The current study has characterized the role of PDK1 in the pathology caused by deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). PDK1 is shown to be essential for lymphomagenesis caused by deletion of PTEN in T cell progenitors. However, PTEN deletion bypasses the normal PDK1-controlled signaling pathways that determine thymocyte growth and proliferation. PDK1 does have important functions in PTEN-null thymocytes, notably to control the PKB-Foxo signaling axis and to direct the repertoire of adhesion and chemokine receptors expressed by PTEN-null T cells. The results thus provide two novel insights concerning pathological signaling caused by PTEN loss in lymphocytes. First, PTEN deletion bypasses the normal PDK1-controlled metabolic checkpoints that determine cell growth and proliferation. Second, PDK1 determines the cohort of chemokine and adhesion receptors expressed by PTEN-null cells, thereby controlling their migratory capacity.


Assuntos
Movimento Celular , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , PTEN Fosfo-Hidrolase/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Linfócitos T/enzimologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Moléculas de Adesão Celular/metabolismo , Proliferação de Células , Fatores de Transcrição Forkhead/metabolismo , Deleção de Genes , Integrases/metabolismo , Tecido Linfoide/citologia , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/enzimologia , Proteína rhoA de Ligação ao GTP/metabolismo
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