Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors

Fabrizio Griffero, Antonio Daga, Daniela Marubbi, Maria Cristina Capra, Alice Melotti, Alessandra Pattarozzi, Monica Gatti, Adriana Bajetto, Carola Porcile, Federica Barbieri, Roberto E. Favoni, Michele Lo Castro, Gianluigi Zona, Renato Spaziante, Tullio Florio, Giorgio Corte

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Abstract

Because a subpopulation of cancer stem cells (tumor-initiating cells, TICs) is believed to be responsible for the development, progression, and recurrence of many tumors, we evaluated the in vitro sensitivity of human glioma TICs to epidermal growth factor receptor (EGFR) kinase inhibitors (erlotinib and gefitinib) and possible molecular determinants for their effects. Cells isolated from seven glioblastomas (GBM 1-7) and grown using neural stem cell permissive conditions were characterized for in vivo tumorigenicity, expression of tumor stem cell markers (CD133, nestin), and multilineage differentiation properties, confirming that these cultures are enriched in TICs. TIC cultures were challenged with increasing concentrations of erlotinib and gefitinib, and their survival was evaluated after 1-4 days. In most cases, a time- and concentration-dependent cell death was observed, although GBM 2 was completely insensitive to both drugs, and GBM 7 was responsive only to the highest concentrations tested. Using a radioligand binding assay, we show that all GBM TICs express EGFR. Erlotinib and gefitinib inhibited EGFR and ERK1/2 phosphorylation/activation in all GBMs, irrespective of the antiproliferative response observed. However, under basal conditions GBM 2 showed a high Akt phosphorylation that was completely insensitive to both drugs, whereas GBM 7 was completely insensitive to gefitinib, and Akt inactivation occurred only for the highest erlotinib concentration tested, showing a precise relationship with the antiproliferative effects of the drug. Interestingly, in GBM 2, phosphatase and tensin homolog expression was significantly down-regulated, possibly accounting for the insensitivity to the drugs. In conclusion, glioma TICs are responsive to anti-EGFR drugs, but phosphatase and tensin homolog expression and Akt inhibition seem to be necessary for such effect.

Original languageEnglish
Pages (from-to)7138-7148
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number11
DOIs
Publication statusPublished - Mar 13 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Griffero, F., Daga, A., Marubbi, D., Capra, M. C., Melotti, A., Pattarozzi, A., Gatti, M., Bajetto, A., Porcile, C., Barbieri, F., Favoni, R. E., Lo Castro, M., Zona, G., Spaziante, R., Florio, T., & Corte, G. (2009). Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors. Journal of Biological Chemistry, 284(11), 7138-7148. https://doi.org/10.1074/jbc.M807111200