DHPS-dependent hypusination of eIF5A1/2 is necessary for TGFß/fibronectin-induced breast cancer metastasis and associates with prognostically unfavorable genomic alterations in TP53.
Biochem Biophys Res Commun
; 519(4): 838-845, 2019 11 19.
Article
en En
| MEDLINE
| ID: mdl-31558321
ABSTRACT
Metastasis is the leading cause of mortality in patients with solid tumors. In this regard, we previously reported that Pseudopodium-Enriched Atypical Kinase One (PEAK1) is necessary for non-canonical Transforming Growth Factor ß (TGFß) signaling and TGFß/fibronectin-induced metastasis. Here, we demonstrate that inhibition of DHPS-dependent eIF5A1/2 hypusination blocks PEAK1 and E-Cadherin expression, breast cancer cell viability and TGFß/fibronectin-induced PEAK1-dependent breast cancer metastasis. Interestingly, TGFß stimulation of high-grade metastatic breast cancer cells increases and sustains eIF5A1/2 hypusination. We used a suite of bioinformatics platforms to search biochemical/functional interactions and clinical databases for additional control points in eIF5A1/2 and PEAK1-Epithelial to Mesenchymal Transition (EPE) pathways. This effort revealed that interacting EPE genes were enriched for TP53 transcriptional targets and were commonly co-amplified in breast cancer patients harboring inactivating TP53 mutations. Taken together, these results suggest that combinatorial therapies targeting DHPS and protein activities elevated in TP53-mutant breast cancers may reduce systemic tumor burden and improve patient outcomes.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Factores de Iniciación de Péptidos
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Proteína p53 Supresora de Tumor
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Factor de Crecimiento Transformador beta
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Fibronectinas
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Proteínas de Unión al ARN
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Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Female
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Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
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US
/
USA