title: The 4E-BP1/eIF4E ratio is a determinant for rapamycin response in esophageal cancer cells.
abstract: OBJECTIVE
  Rapamycin inhibits products of molecular pathways in esophageal squamous cell carcinoma and limits tumor cell growth by targeting 4E-BP1- and eIF4E-dependent gene translation. In this study, we investigate the influence of 4E-BP1-to-eIF4E ratio on rapamycin response in esophageal squamous cell carcinoma cells, and the underlying mechanism is discussed.
  
  
  METHODS
  The response to rapamycin treatment was examined in 6 esophageal cancer cell lines. Adjustment of the 4E-BP1/eIF4E ratio was carried out by knockdown or overexpression of 4E-BP1 and eIF4E. The relationship between Egr-1 and 4E-BP1 expression in esophageal cancer cells was also studied.
  
  
  RESULTS
  The 4E-BP1/eIF4E ratio was adjusted to evaluate the response to rapamycin treatment in TE1 and TE2 esophageal cancer cells. TE2 cells are sensitized to rapamycin treatment after overexpression of 4E-BP1 or knockdown of eIF4E; TE1 cells become resistant to rapamycin after knockdown of 4E-BP1 or overexpression of eIF4E. These data suggest that the 4E-BP1/eIF4E ratio is a determinant for the response of TE1 and TE2 cells to rapamycin treatment. Egr-1 expression was higher in TE2 cells compared with other esophageal cancer cell lines, and its knockdown increased 4E-BP1 expression in TE2 cells, which became sensitive to rapamycin treatment.
  
  
  CONCLUSIONS
  The 4E-BP1/eIF4E ratio is a determinant of the response of rapamycin treatment in esophageal cancer cells. Egr-1 can reduce 4E-BP1 gene expression and render esophageal squamous cell carcinoma cells resistant to rapamycin with a relatively low 4E-BP1/eIF4E ratio. Thus, the 4E-BP1/eIF4E ratio may represent a therapeutic index for the prediction of clinical outcome of rapamycin treatment in patients with esophageal squamous cell carcinoma.
authors.affiliation: Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: thcheng@ym.edu.tw.
authors.forename: Han-Shui
authors.initials: HS
authors.lastname: Hsu
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan; Division of Nuclear Medicine, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jang
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Kuo
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chen-Chi
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Cheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D039562:Eukaryotic Initiation Factor-4F / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C497325:EGR1 protein, human; C087000:EIF4EBP1 protein, human; D051766:Early Growth Response Protein 1; D039562:Eukaryotic Initiation Factor-4F; D010750:Phosphoproteins; D020123:Sirolimus