Time-dependent effects of hypoxia on cell metabolism, signaling, and iron homeostasis in the hematopoietic progenitor model KG1a.
FEBS Open Bio
; 13(7): 1291-1308, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-36416440
ABSTRACT
Lowered availability of oxygen in the micro-environment of cells perturbs metabolic and signaling pathways. It affects proliferation, tissue morphology, and differentiation. Leukemia impairs maturation of hematopoietic progenitors the immune system, healing, and erythropoiesis are weakened, thereby perturbing iron homeostasis and further lowering oxygen provision to tissues. Here, the time-dependent molecular consequences of sudden hypoxia were studied in the KG1a model of immature hematopoietic progenitors. The oxygen tension of KG1a cells was abruptly lowered from the experimentally usual ca. 20 to 1%. Growth and key hubs of signaling, metabolism, and iron homeostasis were monitored by a combination of immunological methods and functional assays. The collapse of oxygen availability stopped proliferation after one generation. The number of cells then remained approximately constant over several days, including after anaerobic changes in the culture medium. Lowered oxygen resulted in transient increase of the hypoxia-inducible factor 1α and of its REDD1 target, inhibition of mechanistic (or mammalian) target of rapamycin, decreased autophagy, altered cap-dependent translation, and minimal repression of the already weak oxidative phosphorylation. These adjustments did not trigger important cellular iron fluxes since the cells relied on their internal iron stores to survive. In conclusion, the response of the KG1a cells to stringent hypoxia is varied, with some established hypoxia-sensitive pathways exhibiting activation whereas others were unaffected. The results draw attention to the flexibility of the environmental adaptation of cancer cells. They suggest that thorough characterization of early leukemic blasts is warranted to propose informed treatments to patients.
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1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Ferro
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
FEBS Open Bio
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
França