Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.
Nature
; 524(7565): 361-5, 2015 Aug 20.
Article
em En
| MEDLINE
| ID: mdl-26168401
ABSTRACT
Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins--MITF, TFE3 and TFEB--are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Autofagia
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Fatores de Transcrição
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Regulação Neoplásica da Expressão Gênica
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Carcinoma Ductal Pancreático
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Lisossomos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article