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The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells
被引:255
作者:
Nepstad, Ina
[1
]
Hatfield, Kimberley Joanne
[1
,2
]
Gronningsaeter, Ida Sofie
[1
,3
]
Reikvam, Hakon
[1
,3
]
机构:
[1] Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway
[2] Haukeland Hosp, Dept Immunol & Transfus Med, N-5021 Bergen, Norway
[3] Haukeland Hosp, Dept Med, N-5021 Bergen, Norway
关键词:
Akt;
AML;
chemotherapy;
metabolism;
mTOR;
PI3K;
signaling;
ACUTE MYELOGENOUS LEUKEMIA;
MAMMALIAN TARGET;
STEM-CELLS;
OLDER PATIENTS;
CONSTITUTIVE ACTIVATION;
RAPAMYCIN INHIBITOR;
AKT PHOSPHORYLATION;
P110-DELTA ISOFORM;
TUMOR-SUPPRESSOR;
MTOR INHIBITOR;
D O I:
10.3390/ijms21082907
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of hematopoietic stem cells in the bone marrow. Malignant cell growth is characterized by disruption of normal intracellular signaling, caused by mutations or aberrant external signaling. The phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway (PI3K-Akt-mTOR pathway) is among one of the intracellular pathways aberrantly upregulated in cancers including AML. Activation of this pathway seems important in leukemogenesis, and given the central role of this pathway in metabolism, the bioenergetics of AML cells may depend on downstream signaling within this pathway. Furthermore, observations suggest that constitutive activation of the PI3K-Akt-mTOR pathway differs between patients, and that increased activity within this pathway is an adverse prognostic parameter in AML. Pharmacological targeting of the PI3K-Akt-mTOR pathway with specific inhibitors results in suppression of leukemic cell growth. However, AML patients seem to differ regarding their susceptibility to various small-molecule inhibitors, reflecting biological heterogeneity in the intracellular signaling status. These findings should be further investigated in both preclinical and clinical settings, along with the potential use of this pathway as a prognostic biomarker, both in patients receiving intensive curative AML treatment and in elderly/unfit receiving AML-stabilizing treatment.
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