Atg7 suppression enhances chemotherapeutic agent sensitivity and overcomes stroma-mediated chemoresistance in acute myeloid leukemia.
Blood
; 128(9): 1260-9, 2016 09 01.
Article
en En
| MEDLINE
| ID: mdl-27268264
ABSTRACT
Autophagy is a cellular adaptive mechanism to stress, including that induced by chemotherapeutic agents. Reverse phase protein array suggested that high expression of the essential autophagy-related protein, Atg7, was associated with shorter remission in newly diagnosed acute myeloid leukemia (AML) patient samples, indicating a role in chemoresistance. Knockdown of Atg7 in AML cells using short hairpin RNA markedly increased apoptosis and DNA damage following treatment with cytarabine and idarubicin. Interestingly, coculture of AML cells with stromal cells increased autophagy and chemoresistance in the AML cells exposed to chemotherapeutic agents, and this was reversed following Atg7 knockdown. This effect was further enhanced by concomitant knockdown of Atg7 in both AML and stromal cells. These findings strongly suggest that Atg7, and likely microenvironment autophagy in general, plays an important role in AML chemoresistance. Mechanistic studies revealed that Atg7 knockdown induced a proapoptotic phenotype in AML cells, which was manifested by an increased NOXA expression at the transcriptional level. Finally, in a mouse model of human leukemia, Atg7 knockdown extended overall survival after chemotherapy. Thus, the inhibition of Atg7 appears to be a valid strategy to enhance chemosensitivity, and it could indeed improve outcomes in AML therapy.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Autofagia
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Leucemia Mieloide Aguda
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Resistencia a Antineoplásicos
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Microambiente Tumoral
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Proteína 7 Relacionada con la Autofagia
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Blood
Año:
2016
Tipo del documento:
Article