Abstract
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 p110β and p110δ 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kelly LM, Gilliland DG . Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet 2002; 3: 179–198.
Meshinchi S, Smith FO, Arceci RJ . Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia. Curr Oncol Rep 2003; 5: 489–497.
Bieker R, Padro T, Kramer J, Steins M, Kessler T, Retzlaff S et al. Overexpression of basic fibroblast growth factor and autocrine stimulation in acute myeloid leukemia. Cancer Res 2003; 63: 7241–7246.
Fiedler W, Graeven U, Ergun S, Verago S, Kilic N, Stockschlader M et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood 1997; 89: 1870–1875.
Zheng R, Levis M, Piloto O, Brown P, Baldwin BR, Gorin NC et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 2004; 103: 267–274.
Gilliland DG, Griffin JD . The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100: 1532–1542.
Ikeda H, Kanakura Y, Tamaki T, Kuriu A, Kitayama H, Ishikawa J et al. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood 1991; 78: 2962–2968.
Aguayo A, Estey E, Kantarjian H, Mansouri T, Gidel C, Keating M et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood 1999; 94: 3717–3721.
Tse KF, Allebach J, Levis M, Smith BD, Bohmer FD, Small D . Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia 2002; 16: 2027–2036.
O'Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101: 3597–3605.
Brown P, Small D . FLT3 inhibitors: a paradigm for the development of targeted therapeutics for paediatric cancer. Eur J Cancer 2004; 40: 707–721; discussion 22–4.
Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE . The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000; 21: 215–244.
Hizuka N, Sukegawa I, Takano K, Asakawa K, Horikawa R, Tsushima T et al. Characterization of insulin-like growth factor I receptors on human erythroleukemia cell line (K-562 cells). Endocrinol Jpn 1987; 34: 81–88.
Sukegawa I, Hizuka N, Takano K, Asakawa K, Shizume K . Decrease in IGF-I binding sites on human promyelocytic leukemia cell line (HL-60) with differentiation. Endocrinol Jpn 1987; 34: 365–372.
Neri LM, Borgatti P, Tazzari PL, Bortul R, Cappellini A, Tabellini G et al. The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells. Mol Cancer Res 2003; 1: 234–246.
Yasui H, Hideshima T, Richardson PG, Anderson KC . Novel therapeutic strategies targeting growth factor signalling cascades in multiple myeloma. Br J Haematol 2006; 132: 385–397.
Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 2004; 5: 221–230.
Yamamoto K, Altschuler D, Wood E, Horlick K, Jacobs S, Lapetina EG . Association of phosphorylated insulin-like growth factor-I receptor with the SH2 domains of phosphatidylinositol 3-kinase p85. J Biol Chem 1992; 267: 11337–11343.
Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD . Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 1997; 22: 267–272.
Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD . Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001; 17: 615–675.
Aggerholm A, Gronbaek K, Guldberg P, Hokland P . Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol 2000; 65: 109–113.
Maehama T, Dixon JE . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375–13378.
Kang S, Bader AG, Vogt PK . Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 2005; 102: 802–807.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304: 554.
Liu TC, Lin PM, Chang JG, Lee JP, Chen TP, Lin SF . Mutation analysis of PTEN/MMAC1 in acute myeloid leukemia. Am J Hematol 2000; 63: 170–175.
Hummerdal P, Andersson P, Willander K, Linderholm M, Soderkvist P, Jonsson JI . Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia. Eur J Haematol 2006; 77: 86–87.
Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M . Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003; 102: 972–980.
Grandage VL, Gale RE, Linch DC, Khwaja A . PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia 2005; 19: 586–594.
Fukuda R, Hayashi A, Utsunomiya A, Nukada Y, Fukui R, Itoh K et al. Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL). Proc Natl Acad Sci USA 2005; 102: 15213–15218.
Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J et al. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 2004; 5: 231–239.
Marra G, D'Atri S, Corti C, Bonmassar L, Cattaruzza MS, Schweizer P et al. Tolerance of human MSH2+/− lymphoblastoid cells to the methylating agent temozolomide. Proc Natl Acad Sci USA 2001; 98: 7164–7169.
Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M et al. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 2004; 428: 431–437.
Guerreiro AS, Boller D, Shalaby T, Grotzer MA, Arcaro A . Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin-like growth factor receptor inhibition. Int J Cancer 2006; 119: 2527–2538.
Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 2005; 11: 507–514.
Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE . Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement. J Immunol 2003; 170: 2647–2654.
Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000; 6: 2053–2063.
Grundler R, Thiede C, Miething C, Steudel C, Peschel C, Duyster J . Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood 2003; 102: 646–651.
Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005; 105: 54–60.
Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.
Nakanishi Y, Mulshine JL, Kasprzyk PG, Natale RB, Maneckjee R, Avis I et al. Insulin-like growth factor-I can mediate autocrine proliferation of human small cell lung cancer cell lines in vitro. J Clin Invest 1988; 82: 354–359.
Shimon I, Shpilberg O . The insulin-like growth factor system in regulation of normal and malignant hematopoiesis. Leuk Res 1995; 19: 233–240.
Dawczynski K, Kauf E, Zintl F . Changes of serum growth factors (IGF-I, -II and IGFBP-2, -3) prior to and after stem cell transplantation in children with acute leukemia. Bone Marrow Transplant 2003; 32: 411–415.
Warshamana-Greene GS, Litz J, Buchdunger E, Hofmann F, Garcia-Echeverria C, Krystal GW . The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVP-ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signaling. Mol Cancer Ther 2004; 3: 527–535.
Bertrand FE, Steelman LS, Chappell WH, Abrams SL, Shelton JG, White ER et al. Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells. Leukemia 2006; 20: 1254–1260.
Warshamana-Greene GS, Litz J, Buchdunger E, Garcia-Echeverria C, Hofmann F, Krystal GW . The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 2005; 11: 1563–1571.
Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006; 20: 911–928.
Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F et al. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 2005; 106: 1063–1066.
Billottet C, Grandage VL, Gale RE, Quattropani A, Rommel C, Vanhaesebroeck B et al. A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene 2006; 25: 6648–6659.
Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E et al. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 2006; 441: 366–370.
Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006; 125: 733–747.
Hooshmand-Rad R, Hajkova L, Klint P, Karlsson R, Vanhaesebroeck B, Claesson-Welsh L et al. The PI 3-kinase isoforms p110(alpha) and p110(beta) have differential roles in PDGF- and insulin-mediated signaling. J Cell Sci 2000; 113 (Part 2): 207–214.
Acknowledgements
We thank M Lambelet for isolating AML blasts. We thank Drs F Hofmann and MA Pearson (Novartis Pharma) for providing NVP-AEW541. We thank Dr SP Jackson (Australian Center for Blood Diseases) for providing TGX-221 and Dr JS Hayflick (ICOS Corporation) for providing IC87114. We thank Drs J Jiricny, OE Pardo, J Downward, SP Jackson and A Klippel for providing reagents and cell lines. This work was supported by a grant from the Krebsliga Zürich to AA.
Author information
Authors and Affiliations
Corresponding author
Additional information
Research Support: Krebsliga Zürich.
Supplementary Information accompanies the paper on the Leukemia web site (http://www.nature.com/leu)
Rights and permissions
About this article
Cite this article
Doepfner, K., Spertini, O. & Arcaro, A. Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway. Leukemia 21, 1921–1930 (2007). https://doi.org/10.1038/sj.leu.2404813
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2404813
Keywords
This article is cited by
-
Insulin-like growth factor 1 receptor inhibits the proliferation of acute myeloid leukaemia cells via NK cell activation
Annals of Hematology (2023)
-
Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway
Leukemia (2022)
-
The regulatory ZFAS1/miR-150/ST6GAL1 crosstalk modulates sialylation of EGFR via PI3K/Akt pathway in T-cell acute lymphoblastic leukemia
Journal of Experimental & Clinical Cancer Research (2019)
-
IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights
Molecular Cancer (2017)
-
IGF1R+ Dental Pulp Stem Cells Enhanced Neuroplasticity in Hypoxia-Ischemia Model
Molecular Neurobiology (2017)