Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts.
Leukemia
; 21(3): 427-38, 2007 Mar.
Article
in En
| MEDLINE
| ID: mdl-17215852
ABSTRACT
A high incidence of relapses following induction chemotherapy is a major hindrance to patient survival in acute myelogenous leukemia (AML). There is strong evidence that activation of the phosphoinositide 3 kinase (PI3K)/Akt signaling network plays a significant role in rendering AML blasts drug resistant. An important mechanism underlying drug resistance is represented by overexpression of membrane drug transporters such as multidrug resistance-associated protein 1 (MRP1) or 170-kDa P-glycoprotein (P-gp). Here, we present evidence that MRP1, but not P-gp, expression is under the control of the PI3K/Akt axis in AML blasts. We observed a highly significant correlation between levels of phosphorylated Akt and MRP1 expression in AML cells. Furthermore, incubation of AML blasts with wortmannin, a PI3K pharmacological inhibitor, resulted in lower levels of phosphorylated Akt, downregulated MRP1 expression, and decreased Rhodamine 123 extrusion in an in vitro functional dye efflux assay. We also demonstrate that wortmannin-dependent PI3K/Akt inhibition upregulated p53 protein levels in most AML cases, and this correlated with diminished MRP1 expression and enhanced phosphorylation of murine double minute 2 (MDM2). Taken together, these data suggest that PI3K/Akt activation may lead to the development of chemoresistance in AML blasts through a mechanism involving a p53-dependent suppression of MRP1 expression.
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Collection:
01-internacional
Health context:
2_ODS3
/
6_ODS3_enfermedades_notrasmisibles
Database:
MEDLINE
Main subject:
Leukemia, Myeloid
/
Gene Expression Regulation, Leukemic
/
Drug Resistance, Neoplasm
/
Phosphatidylinositol 3-Kinases
/
Multidrug Resistance-Associated Proteins
/
Proto-Oncogene Proteins c-akt
Type of study:
Risk_factors_studies
Limits:
Aged80
Language:
En
Journal:
Leukemia
Year:
2007
Document type:
Article