title: AKT and MET signalling mediates antiapoptotic radioresistance in head neck cancer cell lines.
abstract: OBJECTIVE
  Induction of apoptosis is a major mechanism of radiosensitivity in different types of cancer. In contrast, EGFR/PI3K/AKT signalling and recently the presence of so-called cancer stem cells are discussed as reasons for radioresistance.
  
  
  METHODS
  The study investigates mechanisms of apoptosis, key oncogenes of the PI3K/AKT pathway and the presence of cancer cells with stem cell properties during irradiation in two cell lines (PCI-9A, and PCI-15) of head and neck squamous cell carcinoma. WST-1-tests, qRT-PCR, western blots and FACS analysis were performed for analysis.
  
  
  RESULTS
  The two cell lines presented different degrees of cell death upon irradiation. The radiosensitive cell line PCI-9A showed increased apoptosis after irradiation measured by expressed cleaved caspases 3 and 7 while the radioresistant cell line PCI-15 upregulated antiapoptotic Survivin and BCL2A1 mRNA. Besides, increased PI3K/AKT- and ERK1/2-signalling was associated with radioresistance accompanied by loss of PTEN function through phosphorylation on S380. Blockade of pAKT increased radiation-induced cell death, and moreover, led to an upregulation of pMET in the radioresistant cell line. The percentage of ALDH-positive tumour cells was markedly decreased after irradiation in the radiosensitive cell line.
  
  
  CONCLUSIONS
  Functional apoptosis is mandatory for sensitivity to irradiation in head neck cancer cells. Upregulation of the AKT-pathway seems to be one reason for poor radioresponse. Activated MET may also predict radioresistance, possibly through ERK1/2 signalling. Moreover MET may indicate the presence of cancer stem cells facilitating radioresistance as shown by increased ALDH expression.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: tobias.ettl@ukr.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ettl
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: sandra.viale-bouroncle@ukr.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Viale-Bouroncle
authors.affiliation: Department of Radiotherapy, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: matthias.hautmann@ukr.de.
authors.forename: Matthias G
authors.initials: MG
authors.lastname: Hautmann
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: martin.gosau@ukr.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Gosau
authors.affiliation: Department of Radiotherapy, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: oliver.koelbl@ukr.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kölbl
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: torsten.reichert@ukr.de.
authors.forename: Torsten E
authors.initials: TE
authors.lastname: Reichert
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany. Electronic address: christian.morsczeck@ukr.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Morsczeck
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011836:Radiation Tolerance; D015398:Signal Transduction
chemical_list: D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; ALDH; Apoptosis; Head neck cancer; Irradiation; MET; Stem cells