Article: article d'un périodique ou d'un magazine.
Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway
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Journal Article Research Support, Non-U.S. Gov't --- Old month value: Sep
Insulin-like growth factor (IGF) signaling plays an important role in various human cancers. Therefore, the role of insulin-like growth factor I (IGF-I) signaling in growth and survival of acute myeloid leukemia (AML) cells was investigated. Expression of the IGF-I receptor (IGF-IR) and its ligand IGF-I were detected in a panel of human AML blasts and cell lines. IGF-I and insulin promoted the growth of human AML blasts in vitro and activated the phosphoinositide 3-kinase (PI3K)/Akt and the extracellular signal-regulated kinase (Erk) pathways. IGF-I-stimulated growth of AML blasts was blocked by an inhibitor of the PI3K/Akt pathway. Moreover, downregulation of the class Ia PI3K isoforms p110beta and p110delta by RNA interference impaired IGF-I-stimulated Akt activation, cell growth and survival in AML cells. Proliferation of a panel of AML cell lines and blasts isolated from patients with AML was inhibited by the IGF-IR kinase inhibitor NVP-AEW541 or by an IGF-IR neutralizing antibody. In addition to its antiproliferative effects, NVP-AEW541 sensitized primary AML blasts and cell lines to etoposide-induced apoptosis. Together, our data describe a novel role for autocrine IGF-I signaling in the growth and survival of primary AML cells. IGF-IR inhibitors in combination with chemotherapeutic agents may represent a novel approach to target human AML.
1-Phosphatidylinositol 3-Kinase/*metabolism Acute Disease Antibodies/pharmacology Antimetabolites, Antineoplastic/pharmacology Antineoplastic Agents, Phytogenic/pharmacology Apoptosis/drug effects/physiology Autocrine Communication Cell Division/physiology Cell Line, Tumor Cytarabine/pharmacology Down-Regulation Etoposide/pharmacology Humans Insulin-Like Growth Factor I/*metabolism Leukemia, Myeloid/metabolism/*pathology Proto-Oncogene Proteins c-akt/*metabolism Receptor, IGF Type 1/immunology/metabolism Signal Transduction/*physiology
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