A cisplatin-resistant head and neck cancer cell line with cytoplasmic p53mut exhibits ATP-binding cassette transporter upregulation and high glutathione levels

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• 作者：Manuel Tonigold (1)
  Annette Rossmann (1) (2)
  Marie Meinold (1)
  Michael Bette (2)
  Melanie M盲rken (3)
  Katharina Henkenius (3)
  Anne C. Bretz (4)
  Gavin Giel (3)
  Chengzhong Cai (1)
  Fiona R. Rodepeter (1)
  Vladimir Bene拧 (5)
  Reidar Gr茅nman (6)
  Thomas E. Carey (7)
  Hermann Lage (8)
  Thorsten Stiewe (4)
  Andreas Neubauer (3)
  Jochen A. Werner (1)
  Cornelia Brendel (3)
  Robert Mandic (1)
  
• 关键词：HNSCC ; p53 ; Cisplatin ; ABC transporter ; Metabolism ; Glutathione
• 刊名：Journal of Cancer Research and Clinical Oncology
• 出版年：2014
• 出版时间：October 2014
• 年：2014
• 卷：140
• 期：10
• 页码：1689-1704
• 全文大小：2,393 KB
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• 作者单位：Manuel Tonigold (1)
  Annette Rossmann (1) (2)
  Marie Meinold (1)
  Michael Bette (2)
  Melanie M盲rken (3)
  Katharina Henkenius (3)
  Anne C. Bretz (4)
  Gavin Giel (3)
  Chengzhong Cai (1)
  Fiona R. Rodepeter (1)
  Vladimir Bene拧 (5)
  Reidar Gr茅nman (6)
  Thomas E. Carey (7)
  Hermann Lage (8)
  Thorsten Stiewe (4)
  Andreas Neubauer (3)
  Jochen A. Werner (1)
  Cornelia Brendel (3)
  Robert Mandic (1)
  
  1. Department of Otolaryngology, Head and Neck Surgery, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35033, Marburg, Germany
  2. Institute of Anatomy and Cell Biology, Philipps University, Robert-Koch-Strasse 8, 35037, Marburg, Germany
  3. Department of Hematology, Oncology and Immunology, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35033, Marburg, Germany
  4. Department of Molecular Oncology, Philipps-University, Hans-Meerwein-Str. 3, 35043, Marburg, Germany
  5. Genomics Core Facility, European Molecular Biology Laboratory, Meyerhofstr. 1, 69117, Heidelberg, Germany
  6. Department of Otorhinolaryngology - Head and Neck Surgery, Turku University and Turku University Central Hospital, P.O.Box 52, 20521, Turku, Finland
  7. Department of Otolaryngology-HNS, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
  8. Institute of Pathology, Charit茅 - Universit盲tsmedizin Berlin, Campus Mitte, Charit茅platz 1, 10117, Berlin, Germany
  
• ISSN：1432-1335

文摘

Purpose Head and neck squamous cell carcinoma (HNSCC) cell lines with cytoplasmically sequestered mutant p53 (p53mut_c) are frequently more resistant to cisplatin (CDDP) than cells with mutant but nuclear p53 (p53mut_n). The aim of the study was to identify underlying mechanisms implicated in CDDP resistance of HNSCC cells carrying cytoplasmic p53mut. Methods Microarray analysis, quantitative reverse transcription polymerase chain reaction, Western blot analysis and immunocytochemistry were used to identify and evaluate candidate genes involved in CDDP resistance of p53mut_c cells. RNAi knockdown or treatment with inhibitors together with flow cytometry-based methods was used for functional assessment of the identified candidate genes. Cellular metabolic activity was assessed with the XTT assay, and the redox capacity of cells was evaluated by measuring cellular glutathione (GSH) levels. Results Upregulation of ABCC2 and ABCG2 transporters was observed in CDDP-resistant p53mut_c HNSCC cells. Furthermore, p53mut_c cells exhibited a pronounced side population that could be suppressed by RNAi knockdown of ABCG2 as well as treatment with the ATP-binding-cassette transporter inhibitors imatinib, MK571 and tariquidar. Metabolic activity and cellular GSH levels were higher in CDDP-resistant p53mut_c cells, consistent with a higher capacity to fend off cytotoxic oxidative effects such as those caused by CDDP treatment. Finally, ABCC2/G2 inhibition of HNSCC cells with MK571 markedly enhanced CDDP sensitivity of HNSCC cells. Conclusions The observations in this study point to a major role of p53mut_c in conferring a stem cell like phenotype to HNSCC cells that is associated with ABCC2/G2 overexpression, high GSH and metabolic activity levels as well as CDDP resistance.