Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Nature ; 585(7826): 603-608, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32939090

RESUMO

Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2-5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.


Assuntos
Éteres/metabolismo , Ferroptose , Peroxissomos/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Linhagem Celular , Éteres/química , Feminino , Edição de Genes , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Peroxidação de Lipídeos , Masculino , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Peroxissomos/genética
2.
Cell Death Dis ; 15(4): 290, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658567

RESUMO

High-grade serous ovarian cancer (HGSOC) represents the most common and lethal subtype of ovarian cancer. Despite initial response to platinum-based standard therapy, patients commonly suffer from relapse that likely originates from drug-tolerant persister (DTP) cells. We generated isogenic clones of treatment-naïve and cisplatin-tolerant persister HGSOC cells. In addition, single-cell RNA sequencing of barcoded cells was performed in a xenograft model with HGSOC cell lines after platinum-based therapy. Published single-cell RNA-sequencing data from neo-adjuvant and non-treated HGSOC patients and patient data from TCGA were analyzed. DTP-derived cells exhibited morphological alterations and upregulation of epithelial-mesenchymal transition (EMT) markers. An aggressive subpopulation of DTP-derived cells showed high expression of the stress marker ATF3. Knockdown of ATF3 enhanced the sensitivity of aggressive DTP-derived cells to cisplatin-induced cell death, implying a role for ATF3 stress response in promoting a drug tolerant persister cell state. Furthermore, single cell lineage tracing to detect transcriptional changes in a HGSOC cell line-derived xenograft relapse model showed that cells derived from relapsed solid tumors express increased levels of EMT and multiple endoplasmic reticulum (ER) stress markers, including ATF3. Single cell RNA sequencing of epithelial cells from four HGSOC patients also identified a small cell population resembling DTP cells in all samples. Moreover, analysis of TCGA data from 259 HGSOC patients revealed a significant progression-free survival advantage for patients with low expression of the ATF3-associated partial EMT genes. These findings suggest that increased ATF3 expression together with partial EMT promote the development of aggressive DTP, and thereby relapse in HGSOC patients.


Assuntos
Fator 3 Ativador da Transcrição , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias Ovarianas , Humanos , Fator 3 Ativador da Transcrição/metabolismo , Fator 3 Ativador da Transcrição/genética , Feminino , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Animais , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
3.
Nat Cell Biol ; 26(9): 1470-1481, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39009641

RESUMO

Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFß stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1.


Assuntos
Transição Epitelial-Mesenquimal , Ferroptose , Fosfolipídeos , Estearoil-CoA Dessaturase , Homeobox 1 de Ligação a E-box em Dedo de Zinco , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Humanos , Linhagem Celular Tumoral , Fosfolipídeos/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/genética , Lipogênese , Regulação Neoplásica da Expressão Gênica , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Dessaturases/genética , Animais , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Fator de Crescimento Transformador beta/metabolismo , Dessaturase de Ácido Graxo Delta-5 , Resistencia a Medicamentos Antineoplásicos , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Graxo Sintase Tipo I/genética
4.
bioRxiv ; 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38562716

RESUMO

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with a high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, leading directly to significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

5.
Cell Rep ; 42(9): 113023, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37691145

RESUMO

Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.


Assuntos
Ferroptose , Fosfatidilinositóis , Linhagem Celular , Ácidos Graxos Insaturados , Fosfatidilinositóis/metabolismo , Fosfolipídeos/metabolismo , Humanos
6.
Nat Cell Biol ; 26(4): 516-518, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38589530
7.
Cancer Res ; 77(3): 790-801, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27940576

RESUMO

Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiologic studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA Here, we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on COX-2 and NF-κB. We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mTORC1 inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, whereas combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports the evaluation of aspirin and PI3K pathway inhibitors as a combination therapy for targeting breast cancer. Cancer Res; 77(3); 790-801. ©2016 AACR.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Técnicas de Silenciamento de Genes , Humanos , Immunoblotting , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Complexos Multiproteicos/metabolismo , Fosfatidilinositol 3-Quinases/genética , Reação em Cadeia da Polimerase , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Oncotarget ; 7(50): 81981-81994, 2016 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-27626181

RESUMO

Long non-coding RNAs (lncRNAs) have been implicated in normal cellular homeostasis as well as pathophysiological conditions, including cancer. Here we performed global gene expression profiling of mammary epithelial cells transformed by oncogenic v-Src, and identified a large subset of uncharacterized lncRNAs potentially involved in breast cancer development. Specifically, our analysis revealed a novel lncRNA, LINC00520 that is upregulated upon ectopic expression of oncogenic v-Src, in a manner that is dependent on the transcription factor STAT3. Similarly, LINC00520 is also increased in mammary epithelial cells transformed by oncogenic PI3K and its expression is decreased upon knockdown of mutant PIK3CA. Additional expression profiling highlight that LINC00520 is elevated in a subset of human breast carcinomas, with preferential enrichment in the basal-like molecular subtype. ShRNA-mediated depletion of LINC00520 results in decreased cell migration and loss of invasive structures in 3D. RNA sequencing analysis uncovers several genes that are differentially expressed upon ectopic expression of LINC00520, a significant subset of which are also induced in v-Src-transformed MCF10A cells. Together, these findings characterize LINC00520 as a lncRNA that is regulated by oncogenic Src, PIK3CA and STAT3, and which may contribute to the molecular etiology of breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Glândulas Mamárias Humanas/enzimologia , Glândulas Mamárias Humanas/patologia , Mutação , Invasividade Neoplásica , Proteína Oncogênica pp60(v-src)/genética , Proteína Oncogênica pp60(v-src)/metabolismo , Interferência de RNA , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Fatores de Tempo , Transfecção , Regulação para Cima
9.
Mol Oncol ; 9(6): 1140-54, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25735562

RESUMO

NFAT transcription factors are key regulators of gene expression in immune cells. In addition, NFAT1-induced genes play diverse roles in mediating the progression of various solid tumors. Here we show that NFAT1 induces the expression of the IL8 gene by binding to its promoter and leading to IL8 secretion. Thapsigargin stimulation of breast cancer cells induces IL8 expression in an NFAT-dependent manner. Moreover, we show that NFAT1-mediated IL8 production promotes the migration of primary human neutrophils in vitro and also promotes neutrophil infiltration in tumor xenografts. Furthermore, expression of active NFAT1 effectively suppresses the growth of nascent and established tumors by a non cell-autonomous mechanism. Evaluation of breast tumor tissue reveals that while the levels of NFAT1 are similar in tumor cells and normal breast epithelium, cells in the tumor stroma express higher levels of NFAT1 compared to normal stroma. Elevated levels of NFAT1 also correlate with increased neutrophil infiltrate in breast tumors. These data point to a mechanism by which NFAT1 orchestrates the communication between breast cancer cells and host neutrophils during breast cancer progression.


Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Interleucina-8/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas de Neoplasias/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Interleucina-8/genética , Camundongos , Camundongos Nus , Fatores de Transcrição NFATC/genética , Proteínas de Neoplasias/genética , Neutrófilos/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA