title: Novel role for insulin as an autocrine growth factor for malignant brain tumour cells.
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.
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland. Alexandre.Arcaro@kispi.unizh.ch
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
authors.forename: Kathrin T
authors.initials: KT
authors.lastname: Doepfner
authors.forename: Danielle
authors.initials: D
authors.lastname: Boller
authors.forename: Ana S
authors.initials: AS
authors.lastname: Guerreiro
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grotzer
authors.forename: Barbara
authors.initials: B
authors.lastname: Fischer
mesh_terms: D019898:Autocrine Communication / Q000187:drug effects; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007223:Infant; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D000071796:SMARCB1 Protein; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D006133:Growth Substances; D007328:Insulin; D007527:Isoenzymes; D034741:RNA, Small Interfering; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt