Novel role for insulin as an autocrine growth factor for malignant brain tumour cells.
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.
Arcaro
Alexandre
A
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland. Alexandre.Arcaro@kispi.unizh.ch
Doepfner
Kathrin T
KT
Boller
Danielle
D
Guerreiro
Ana S
AS
Shalaby
Tarek
T
Jackson
Shaun P
SP
Schoenwaelder
Simone M
SM
Delattre
Olivier
O
Grotzer
Michael A
MA
Fischer
Barbara
B
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
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