Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway

Insulin- like growth factor ( IGF) signaling plays an important role in various human cancers. Therefore, the role of insulinlike 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- Istimulated growth of AML blasts was blocked by an inhibitor of the PI3K/ Akt pathway. Moreover, downregulation of the class Ia PI3K isoforms p110 beta and p110 delta 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, NVPAEW541 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.