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Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways.
- Source :
-
Blood [Blood] 2008 Jan 01; Vol. 111 (1), pp. 379-82. Date of Electronic Publication: 2007 Sep 18. - Publication Year :
- 2008
-
Abstract
- The phosphatidylinositol 3-kinase (PI3K)/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myeloid leukemia (AML). In 19 AML samples with constitutive PI3K/Akt activation, the rapamycin derivative inhibitor everolimus (RAD001) increased Akt phosphorylation. This mTOR C1-mediated Akt up-regulation was explained by an insulin-like growth factor-1 (IGF-1)/IGF-1 receptor autocrine loop: (1) blast cells expressed functional IGF-1 receptors, and IGF-1-induced Akt activation was increased by RAD001, (2) a neutralizing anti-IGF-1R alpha-IR3 monoclonal antibody reversed the RAD001-induced Akt phosphorylation, and (3) autocrine production of IGF-1 was detected in purified blast cells by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. This RAD001-induced PI3K/Akt up-regulation was due to an up-regulated expression of the IRS2 adaptor. Finally, we observed that concomitant inhibition of mTORC1 and PI3K/Akt by RAD001 and IC87114 induced additive antiproliferative effects. Our results suggest that dual inhibition of the mTORC1 complex and the IGF-1/IGF-1R/PI3K/Akt pathway in AML may enhance the efficacy of mTOR inhibitors in treatment of this disease.
- Subjects :
- Cell Division drug effects
Everolimus
Humans
In Vitro Techniques
Mechanistic Target of Rapamycin Complex 1
Multiprotein Complexes
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation drug effects
Proteins
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction drug effects
Sirolimus pharmacology
TOR Serine-Threonine Kinases
Transcription Factors metabolism
Up-Regulation drug effects
Immunosuppressive Agents pharmacology
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute metabolism
Receptor, IGF Type 1 metabolism
Sirolimus analogs & derivatives
Transcription Factors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 111
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 17878402
- Full Text :
- https://doi.org/10.1182/blood-2007-03-080796