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

Biochem J. 2007 Aug 15;406(1):57-66. doi: 10.1042/BJ20070309.

Abstract

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 p110alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autocrine Communication* / drug effects
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Child, Preschool
  • Chromosomal Proteins, Non-Histone / metabolism
  • Culture Media, Serum-Free
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Enzyme Activation / drug effects
  • Female
  • Growth Substances / metabolism*
  • Growth Substances / pharmacology
  • Humans
  • Infant
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin Secretion
  • Isoenzymes / metabolism
  • Male
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / metabolism
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • SMARCB1 Protein
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism

Substances

  • Chromosomal Proteins, Non-Histone
  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • Growth Substances
  • Insulin
  • Isoenzymes
  • RNA, Small Interfering
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt