Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Cell ; 157(2): 382-394, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24725405

RESUMO

Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Metástase Neoplásica , Neoplasias Pancreáticas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteína Supressora de Tumor p53/genética
2.
Mol Cell ; 59(2): 243-57, 2015 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-26145175

RESUMO

Proteasome inhibition represents a promising strategy of cancer pharmacotherapy, but resistant tumor cells often emerge. Here we show that the microRNA-101 (miR-101) targets the proteasome maturation protein POMP, leading to impaired proteasome assembly and activity, and resulting in accumulation of p53 and cyclin-dependent kinase inhibitors, cell cycle arrest, and apoptosis. miR-101-resistant POMP restores proper turnover of proteasome substrates and re-enables tumor cell growth. In ERα-positive breast cancers, miR-101 and POMP levels are inversely correlated, and high miR-101 expression or low POMP expression associates with prolonged survival. Mechanistically, miR-101 expression or POMP knockdown attenuated estrogen-driven transcription. Finally, suppressing POMP is sufficient to overcome tumor cell resistance to the proteasome inhibitor bortezomib. Taken together, proteasome activity can not only be manipulated through drugs, but is also subject to endogenous regulation through miR-101, which targets proteasome biogenesis to control overall protein turnover and tumor cell proliferation.


Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Inibidores de Proteassoma/metabolismo , Regiões 3' não Traduzidas , Animais , Apoptose , Ácidos Borônicos/farmacologia , Bortezomib , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Células HCT116 , Células Hep G2 , Humanos , Células MCF-7 , Camundongos , Chaperonas Moleculares/antagonistas & inibidores , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologia , RNA Interferente Pequeno/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Proc Natl Acad Sci U S A ; 114(50): 13254-13259, 2017 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-29162693

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of ΔNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a ΔNp63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that ∆Np63 is capable of sustaining the production of HA levels in cell culture and in vivo by regulating the expression of the HA synthase HAS3 and two hyaluronidase genes, HYAL-1 and HYAL-3. In addition, ∆Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, ∆Np63 sustains the epithelial growth factor receptor (EGF-R) activation and the expression of ABCC1 multidrug transporter gene, thus contributing to tumor cell proliferation and chemoresistance. Importantly, p63 expression is positively correlated with CD44, HAS3, and ABCC1 expression in squamous cell carcinoma datasets and p63-HA pathway is a negative prognostic factor of HNSCC patient survival. Altogether, our data shed light on a ∆Np63-dependent pathway functionally important to the regulation of HNSCC progression.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Ácido Hialurônico/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/genética , Carcinogênese/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Hialuronan Sintases/genética , Hialuronan Sintases/metabolismo , Ácido Hialurônico/genética , Hialuronoglucosaminidase/genética , Hialuronoglucosaminidase/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Ativação Transcricional , Proteínas Supressoras de Tumor/genética
4.
Proc Natl Acad Sci U S A ; 113(29): 8290-5, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27357679

RESUMO

Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.


Assuntos
Ácido Graxo Sintase Tipo I/metabolismo , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Pessoa de Meia-Idade , PPAR gama/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transposases
5.
Br J Cancer ; 119(7): 855-863, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30287917

RESUMO

BACKGROUND: Human cancers can be classified based on gene signatures quantifying the degree of cell proliferation and tissue remodelling (PR). However, the specific factors that drive the increased tissue remodelling in tumours are not fully understood. Here we address this question using colorectal cancer as a case study. METHODS: We reanalysed a reported cohort of colorectal cancer patients. The patients were stratified based on gene signatures of cell proliferation and tissue remodelling. Putative transcription factors activity was inferred using gene expression profiles and annotations of transcription factor targets as input. RESULTS: We demonstrate that the PR classification performs better than the currently adopted consensus molecular subtyping (CMS). Although CMS classification differentiates patients with a mesenchymal signature, it cannot distinguish the remaining patients based on survival. We demonstrate that the missing factor is cell proliferation, which is indicative of good prognosis. We also uncover a KLF4 transcription factor activity score associated with the tissue remodelling gene signature. We further show that the KLF4 activity score is significantly higher in colorectal tumours with predicted infiltration of cells from the myeloid lineage. CONCLUSION: The KLF4 activity score is associated with tissue remodelling, myeloid cell infiltration and poor prognosis in colorectal cancer.


Assuntos
Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica/métodos , Fatores de Transcrição Kruppel-Like/genética , Células Mieloides/química , Regulação para Cima , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 4 Semelhante a Kruppel , Masculino , Prognóstico , Análise de Sobrevida
6.
J Cell Sci ; 129(18): 3367-73, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27635066

RESUMO

A defining hallmark of cancer is uncontrolled cell proliferation. This is initiated once cells have accumulated alterations in signaling pathways that control metabolism and proliferation, wherein the metabolic alterations provide the energetic and anabolic demands of enhanced cell proliferation. How these metabolic requirements are satisfied depends, in part, on the tumor microenvironment, which determines the availability of nutrients and oxygen. In this Cell Science at a Glance paper and the accompanying poster, we summarize our current understanding of cancer metabolism, emphasizing pathways of nutrient utilization and metabolism that either appear or have been proven essential for cancer cells. We also review how this knowledge has contributed to the development of anticancer therapies that target cancer metabolism.


Assuntos
Neoplasias/metabolismo , Animais , Ácidos Graxos/biossíntese , Humanos , Redes e Vias Metabólicas , Metaboloma , Metilação , Espécies Reativas de Oxigênio/metabolismo
7.
Proc Natl Acad Sci U S A ; 112(1): 226-31, 2015 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-25535359

RESUMO

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteólise , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Linhagem Celular Tumoral , Progressão da Doença , Deleção de Genes , Humanos , Técnicas In Vitro , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Neovascularização Patológica , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Análise de Sobrevida , Proteína Tumoral p73 , Ubiquitina/metabolismo , Ubiquitinação , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Proc Natl Acad Sci U S A ; 109(38): 15312-7, 2012 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-22949650

RESUMO

p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, ΔNp63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Fosfoproteínas/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Metástase Neoplásica , Transplante de Neoplasias , Isoformas de Proteínas
9.
Proc Natl Acad Sci U S A ; 108(52): 21276-81, 2011 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-22123976

RESUMO

High Gleason score is currently the best prognostic indicator for poor prognosis in prostate cancer. However, a significant number of patients with low Gleason scores develop aggressive disease as well. In an effort to understand molecular signatures associated with poor outcome in prostate cancer, we analyzed a microarray dataset characterizing 281 prostate cancers from a Swedish watchful-waiting cohort. Patients were classified on the basis of their mRNA microarray signature profiles indicating embryonic stem cell expression patterns (stemness), inactivation of the tumor suppressors p53 and PTEN, activation of several oncogenic pathways, and the TMPRSS2-ERG fusion. Unsupervised clustering identified a subset of tumors manifesting stem-like signatures together with p53 and PTEN inactivation, which had very poor survival outcome, a second group with intermediate survival outcome, characterized by the TMPRSS2-ERG fusion, and three groups with benign outcome. The stratification was validated on a second independent dataset of 150 tumor and metastatic samples from a clinical cohort at Memorial Sloan-Kettering Cancer Center. This classification is independent of Gleason score and therefore provides useful unique molecular profiles for prostate cancer prognosis, helping to predict poor outcome in patients with low or average Gleason scores.


Assuntos
Gradação de Tumores/métodos , Neoplasias da Próstata/classificação , Neoplasias da Próstata/genética , RNA Mensageiro , Teorema de Bayes , Células-Tronco Embrionárias/metabolismo , Perfilação da Expressão Gênica , Humanos , Masculino , Análise em Microsséries , Proteínas de Fusão Oncogênica/metabolismo , PTEN Fosfo-Hidrolase/genética , Prognóstico , Suécia , Proteína Supressora de Tumor p53/genética , Conduta Expectante
10.
Front Cell Dev Biol ; 10: 910040, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092714

RESUMO

The therapeutic potential of pluripotent stem cells is great as they promise to usher in a new era of medicine where cells or organs may be prescribed to replace dysfunctional tissue. At the forefront are efforts in the eye to develop this technology as it lends itself to in vivo monitoring and sophisticated non-invasive imaging modalities. In the retina, retinal pigment epithelium (RPE) is the most promising replacement cell as it has a single layer, is relatively simple to transplant, and is associated with several eye diseases. However, after transplantation, the cells may transform and cause complications. This transformation may be partially due to incomplete maturation. With the goal of learning how to mature RPE, we compared induced pluripotent stem cell-derived RPE (iPSC-RPE) cells with adult human primary RPE (ahRPE) cells and the immortalized human ARPE-19 line. We cultured ARPE-19, iPSC-RPE, and ahRPE cells for one month, and evaluated morphology, RPE marker staining, and transepithelial electrical resistance (TEER) as quality control indicators. We then isolated RNA for bulk RNA-sequencing and DNA for genotyping. We genotyped ahRPE lines for the top age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR) risk allele polymorphisms. Transcriptome data verified that both adult and iPSC-RPE exhibit similar RPE gene expression signatures, significantly higher than ARPE-19. In addition, in iPSC-RPE, genes relating to stem cell maintenance, retina development, and muscle contraction were significantly upregulated compared to ahRPE. We compared ahRPE to iPSC-RPE in a model of epithelial-mesenchymal transition (EMT) and observed an increased sensitivity of iPSC-RPE to producing contractile aggregates in vitro which resembles incident reports upon transplantation. P38 inhibition was capable of inhibiting iPSC-RPE-derived aggregates. In summary, we find that the transcriptomic signature of iPSC-RPE conveys an immature RPE state which may be ameliorated by targeting "immature" gene regulatory networks.

11.
EMBO Mol Med ; 14(3): e14764, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35014179

RESUMO

Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.


Assuntos
Antagonistas de Androgênios , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia
12.
Nat Commun ; 13(1): 7551, 2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36477656

RESUMO

The pro-tumourigenic role of epithelial TGFß signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFß signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFß signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFß signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFß signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits.


Assuntos
Apoptose , Fator de Crescimento Transformador beta , Humanos , Apoptose/genética
13.
Pharmaceutics ; 13(8)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34452066

RESUMO

Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier.

14.
Nat Commun ; 12(1): 1623, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712589

RESUMO

The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Metástase Neoplásica , Fosfatidilinositóis/metabolismo , Transdução de Sinais , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Fatores de Troca do Nucleotídeo Guanina/genética , Xenoenxertos , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
J Theor Biol ; 264(3): 945-51, 2010 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-20303985

RESUMO

The regulation of the cell state is a complex process involving several components. These complex dynamics can be modeled using Boolean networks, allowing us to explain the existence of different cell states and the transition between them. Boolean models have been introduced both as specific examples and as ensemble or distribution network models. However, current ensemble Boolean network models do not make a systematic distinction between different cell components such as epigenetic factors, gene and transcription factors. Consequently, we still do not understand their relative contributions in controlling the cell fate. In this work we introduce and study higher order Boolean networks, which feature an explicit distinction between the different cell components and the types of interactions between them. We show that the stability of the cell state dynamics can be determined solving the eigenvalue problem of a matrix representing the regulatory interactions and their strengths. The qualitative analysis of this problem indicates that, in addition to the classification into stable and chaotic regimes, the cell state can be simple or complex depending on whether it can be deduced from the independent study of its components or not. Finally, we illustrate how the model can be expanded considering higher levels and higher order dynamics.


Assuntos
Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes , Modelos Genéticos , Fatores de Transcrição/genética , Algoritmos , Animais , Humanos , Cinética , Transdução de Sinais/genética
16.
Prostate Cancer Prostatic Dis ; 23(4): 596-606, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32358577

RESUMO

BACKGROUND: Despite increases in diagnostics and effective treatments, over 300,000 men die from prostate cancer highlighting the need for specific and differentiating biomarkers. AR phosphorylation associates with castrate-resistance, with pARser213 promoting transcriptional activity. We hypothesise that combined pARser81 and pARser213 reduces survival and would benefit from dual-targeting androgen-dependent and Akt-driven disease. METHODS: Immunohistochemistry and immunofluorescence were performed on matched hormone-naive and castrate-resistant prostate cancer samples. TempO-Seq gene profiling was analysed using DESeq2 package. LNCaP-AI cells were stimulated with DHT or EGF. WST-1 assays were performed to determine effects of Enzalutamide and BKM120 on cell viability. RESULTS: Following the development of castrate-resistance, pARser81 expression reduced and pARser213 expression increased. Castrate-resistance pARser81 expression was not associated with survival but high pARser213 expression was associated with reduced survival from relapse. Combined high pARser81 and pARser213 was associated with reduced survival from relapse. pARser81 expression was induced by 10 nM DHT or 10 nM EGF and pARser213 expression was induced by treatment with 10 nM EGF in LNCaP-AI cells. Cell viability was reduced following treatment with 10 nM Enzalutamide and 10 nM BKM120. Eight genes were differentially expressed between hormone-naive and castrate-resistant tumours and twenty-five genes were differentially expressed between castrate-resistant tumours with high and low pARser213 expression. CONCLUSION: Combined pARser81 and pARser213 provides a novel prognostic biomarker for castrate-resistant disease and a potential predictive and therapeutic target for prostate cancer. Further studies will be required to investigate the combined effects of targeting AR and PI3K/AKT signalling.


Assuntos
Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Serina/metabolismo , Idoso , Aminopiridinas/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Benzamidas/farmacologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Masculino , Morfolinas/farmacologia , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Fosfatidilinositol 3-Quinase/química , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Serina/química , Transdução de Sinais , Taxa de Sobrevida
17.
Nat Commun ; 11(1): 2508, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427840

RESUMO

Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineate a subset of proteins consistently associated with ARI resistance and highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), an auxiliary enzyme of beta-oxidation, as a clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates in redox homeostasis by controlling the balance between saturated and unsaturated phospholipids. DECR1 knockout induces ER stress and sensitises CRPC cells to ferroptosis. In vivo, DECR1 deletion impairs lipid metabolism and reduces CRPC tumour growth, emphasizing the importance of DECR1 in the development of treatment resistance.


Assuntos
Metabolismo dos Lipídeos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Neoplasias de Próstata Resistentes à Castração/enzimologia , Antagonistas de Receptores de Andrógenos/administração & dosagem , Progressão da Doença , Homeostase , Humanos , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Fosfolipídeos/metabolismo , Próstata/enzimologia , Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo
18.
Nat Cancer ; 1(10): 998-1009, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33479702

RESUMO

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty-acid synthesis in CNS leukemia, highlighting Stearoyl-CoA desaturase (SCD1) as a key player. In vivo SCD1 overexpression increases CNS disease, whilst genetic or pharmacological inhibition of SCD1 decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Estearoil-CoA Dessaturase , Sistema Nervoso Central/metabolismo , Humanos , Lipogênese , Estearoil-CoA Dessaturase/genética , Microambiente Tumoral
19.
Sci Signal ; 12(567)2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723174

RESUMO

Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Mass spectrometry-based proteomic analysis of the CAF secretome unraveled that hypoxic CAFs contributed to blood vessel abnormalities by altering their secretion of various pro- and anti-angiogenic factors. Hypoxia induced pronounced remodeling of the CAF proteome, including proteins that have not been previously related to this process. Among those, the uncharacterized protein NCBP2-AS2 that we renamed HIAR (hypoxia-induced angiogenesis regulator) was the protein most increased in abundance in hypoxic CAFs. Silencing of HIAR abrogated the pro-angiogenic and pro-migratory function of hypoxic CAFs by decreasing secretion of the pro-angiogenic factor VEGFA and consequently reducing VEGF/VEGFR downstream signaling in the endothelial cells. Our study has identified a regulator of angiogenesis and provides a map of hypoxia-induced molecular alterations in mammary CAFs.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Hipóxia , Neovascularização Patológica/genética , Proteoma/metabolismo , Proteômica/métodos , Transdução de Sinais/genética , Fator A de Crescimento do Endotélio Vascular/genética
20.
Oncogenesis ; 7(8): 65, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30139970

RESUMO

Triple negative breast cancers (TNBC) represent the most aggressive and clinically relevant breast carcinomas. On the basis of specific molecular signature, the majority of TNBC can be classified as basal-like breast carcinoma. Here, we report data showing that in basal-like breast carcinoma cells ΔNp63 is capable of sustaining the production of the hyaluronic acid (HA), one of the major component of the extracellular matrix (ECM). At molecular level, we found that ΔNp63 regulates the expression of HA-related genes, such as the HA synthase HAS3, the hyaluronidase HYAL-1 and CD44, the major HA cell membrane receptor. By controlling this pathway, ∆Np63 contributes to maintain the self-renewal of breast cancer stem cells. Importantly, high HAS3 expression is a negative prognostic factor of TNBC patients. Our data suggest that in basal-type breast carcinoma ∆Np63 might favor a HA-rich microenviroment, which can sustain tumor proliferation and stemness.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA