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Biochem. J. (2007) 406 (57–66) (Printed in Great Britain)

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Novel role for insulin as an autocrine growth factor for malignant brain tumour cells

Alexandre ARCARO*¹, Kathrin T. DOEPFNER*, Danielle BOLLER*, Ana S. GUERREIRO*, Tarek SHALABY†, Shaun P. JACKSON‡, Simone M. SCHOENWAELDER‡, Olivier DELATTRE§, Michael A. GROTZER† and Barbara FISCHER*

*Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland, †Department of Oncology, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland, ‡Australian Centre for Blood Diseases, Monash University, 6th Floor, Burnet Building, Alfred Medical Research and Education Precinct, Prahran, VIC 3181, Australia, §Institut Curie, Laboratoire de Pathologie Moléculaire des Cancers, 26 rue d'Ulm, Paris 75248, France, and INSERM U509, Paris 75248, France

AT/RTs (atypical teratoid/rhabdoid tumours) of the CNS (central nervous system) are childhood malignancies associated with poor survival rates due to resistance to conventional treatments such as chemotherapy. We characterized a panel of human AT/RT and MRT (malignant rhabdoid tumour) cell lines for expression of RTKs (receptor tyrosine kinases) and their involvement in tumour growth and survival. When compared with normal brain tissue, AT/RT cell lines overexpressed the IR (insulin receptor) and the IGFIR (insulin-like growth factor-I receptor). Moreover, insulin was secreted by AT/RT cells grown in serum-free medium. Insulin potently activated Akt (also called protein kinase B) in AT/RT cells, as compared with other growth factors, such as epidermal growth factor. Pharmacological inhibitors, neutralizing antibodies, or RNAi (RNA interference) targeting the IR impaired the growth of AT/RT cell lines and induced apoptosis. Inhibitors of the PI3K (phosphoinositide 3-kinase)/Akt pathway also impaired basal and insulin-stimulated AT/RT cell proliferation. Experiments using RNAi and isoform-specific pharmacological inhibitors established a key role for the class I_A PI3K p110a isoform in AT/RT cell growth and insulin signalling. Taken together, our results reveal a novel role for autocrine signalling by insulin and the IR in growth and survival of malignant human CNS tumour cells via the PI3K/Akt pathway.

Key words: Akt, atypical teratoid/rhabdoid tumour (AT/RT), cell proliferation, central nervous system, insulin-like growth factor (IGF), phosphoinositide 3-kinase (PI3K).

Abbreviations used: AT/RT, atypical teratoid/rhabdoid tumour; CNS, central nervous system; Cy3, indocarbocyanine; DMEM, Dulbecco's modified Eagle's medium; DTT, dithiothreitol; EGF, epidermal growth factor; EGFR, EGF receptor; ERK1/2, extracellular-signal-regulated kinase 1/2; FCS, foetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HA, haemagglutinin; hSNF5, human SNF5; IGF, insulin-like growth factor; IGFBP1, IGF-binding protein 1; IGFIR, IGF-I receptor; IR, insulin receptor; M-6-PR, mannose 6-phosphate receptor; MRT, malignant rhabdoid tumour; mTOR, mammalian target of rapamycin; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; PDX-1, pancreatic duodenal homeobox-1; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RNAi, RNA interference; RTKs, receptor tyrosine kinases; RT, reverse transcriptase; SCF, stem cell factor; shRNA, small-hairpin RNA; siRNAs, small interfering RNAs; S6K, S6 kinase; Tos-Lys-CH₂Cl, tosyl-lysylchloromethane.

¹To whom correspondence should be addressed (email Alexandre.Arcaro@kispi.unizh.ch).

Received 2 March 2007/8 May 2007; accepted 16 May 2007

Published as BJ Immediate Publication 16 May 2007, doi:10.1042/BJ20070309

© The Authors Journal compilation © 2007 Biochemical Society