Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells.
Int J Hematol
; 102(5): 558-68, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26362858
ABSTRACT
The aim of the present study was to investigate the effects of rapamycin and its underlying mechanisms on acute lymphoblastic leukemia (ALL) cells. We found that the p14, p15, and p57 genes were not expressed in ALL cell lines (Molt-4 and Nalm-6) and adult ALL patients, whereas mTOR, 4E-BP1, and p70S6K were highly expressed. In Molt-4 and Nalm-6 cells exposed to rapamycin, cell viability decreased and the cell cycle was arrested at the G1/S phase. Rapamycin restored p14, p15, and p57 gene expression through demethylation of the promoters of these genes. As expected, rapamycin also increased p14 and p15 protein expression in both Molt-4 and Nalm-6 cells, as well as p57 protein expression in Nalm-6 cells. Rapamycin additionally decreased mTOR and p70S6K mRNA levels, as well as p70S6K and p-p70S6K protein levels. However, depletion of mTOR by siRNA did not alter the expression and promoter methylation states of p14, p15, and p57. These results indicate that the inhibitory effect of rapamycin may be due mainly to increased p14, p15, and p57 expression via promoter demethylation and decreased mTOR and p70S6K expression in ALL cell lines. These results suggest a potential role for rapamycin in the treatment of adult ALL.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Regulación Leucémica de la Expresión Génica
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Proteínas Oncogénicas
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Sirolimus
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Proteínas Quinasas S6 Ribosómicas 70-kDa
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Inhibidor p15 de las Quinasas Dependientes de la Ciclina
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Inhibidor p57 de las Quinasas Dependientes de la Ciclina
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
/
Serina-Treonina Quinasas TOR
Límite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Int J Hematol
Asunto de la revista:
HEMATOLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
China