Temozolomide induced c-Myc-mediated apoptosis via Akt signalling in MGMT expressing glioblastoma cells

Maria De Salvo, Giovanna Maresca, Igea D'Agnano, Rodolfo Marchese, Antonio Stigliano, Raffaella Gagliassi, Ercole Brunetti, Giorgio H. Raza, Ugo De Paula, Barbara Bucci

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: We investigated the molecular mechanisms underlying the cytotoxic effect of Temozolomide (TMZ) in both O6-methylguanine-DNA methyl transferase (MGMT) depleted as well as undepleted glioblastoma cell lines. Since TMZ is used in clinics in combination with radiotherapy, we also studied the effects of TMZ in combination with ionising radiation (IR). Methods: Cell colony-forming ability was measured using a clonogenic assay. Cell cycle analysis and apoptosis were evaluated by Flow Cytometry (FCM). Proteins involved in cell cycle control were detected by Western blot and co-immunoprecipitation assays. Results: Our data showed that TMZ, independent of MGMT expression, inhibited glioblastoma cell growth via an irreversible G2 block in MGMT depleted cells or the induction of apoptosis in MGMT normal expressing cells. When TMZ was administered in combination with IR, apoptosis was greater than observed with either agent separately. This TMZ-induced apoptosis in the MGMT expressing cells occurred through Akt/Glycogen-Synthase-Kinase-3ß (GSK3ß) signalling and was mediated by Myelocytomatosis (c-Myc) oncoprotein. Indeed, TMZ phosphorylated/activated Akt led to phosphorylation/inactivation of GSK3ß which resulted in the stabilisation of c-Myc protein and subsequent modulation of the c-Myc target genes involved in the apoptotic processes. Conclusion: c-Myc expression could be considered a good indicator of TMZ effectiveness.

Original languageEnglish
Pages (from-to)518-533
Number of pages16
JournalInternational Journal of Radiation Biology
Volume87
Issue number5
DOIs
Publication statusPublished - May 2011

Keywords

  • Akt/GSK3b pathway
  • apoptosis
  • c-Myc activation
  • glioblastoma cell lines
  • irradiation
  • temozolomide

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

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