title: Targeting polo-like kinase 1 enhances radiation efficacy for head-and-neck squamous cell carcinoma.
abstract: OBJECTIVE
  To investigate the efficacy of targeting polo-like kinase 1 (Plk1) combined with ionizing radiotherapy (RT) for head-and-neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  Polo-like kinase 1 messenger ribonucleic acid (mRNA) was targeted by small interfering RNA (siRNA) transfection into the FaDu HNSCC cell line; reduction was confirmed using quantitative real-time polymerase chain reaction. The cellular effects were assessed using [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium], clonogenic, flow cytometric, and caspase assays. In vivo efficacy of siPlk1 was evaluated using mouse xenograft models.
  
  
  RESULTS
  Small interfering Plk1 significantly decreased Plk1 mRNA expression, while also increasing cyclin B1 and p21(Waf1/CIP1) mRNA levels after 24 h. This depletion resulted in a time-dependent increase in FaDu cytotoxicity, which was enhanced by the addition of RT. Flow cytometric and caspase assays demonstrated progressive apoptosis, DNA double-strand breaks (gamma-H2AX), G2/M arrest, and activation of caspases 3 and 7. Implantation of siPlk1-treated FaDu cells in severe combined immunodeficient mice delayed tumor formation, and systemic administration of siPlk1 inhibited tumor growth enhanced by RT.
  
  
  CONCLUSIONS
  These data demonstrate the suitability of Plk1 as a potential therapeutic target for HNSCC, because Plk1 depletion resulted in significant cytotoxicity in vitro and abrogated tumor-forming potential in vivo. The effects of Plk1 depletion were enhanced with the addition of RT, indicating that Plk1 represents an important potential radiation sensitizer for HNSCC.
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Kate
authors.initials: K
authors.lastname: Gerster
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ng
authors.forename: Shijun
authors.initials: S
authors.lastname: Yue
authors.forename: Emma
authors.initials: E
authors.lastname: Ito
authors.forename: John
authors.initials: J
authors.lastname: Waldron
authors.forename: Ralph
authors.initials: R
authors.lastname: Gilbert
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection; D014410:Tumor Stem Cell Assay / Q000379:methods; D000097869:Polo-Like Kinase 1
chemical_list: D053148:Caspase 3; D053179:Caspase 7; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D000097869:Polo-Like Kinase 1; C493956:CDKN1A protein, human; C468783:H2AX protein, human; C070380:3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium