title: Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells.
abstract: Elevated levels of eukaryotic translation initiation factor 4E (eIF4E) enhance translation of many malignancy-related proteins, such as vascular endothelial growth factor (VEGF), c-Myc and osteopontin. In non-small-cell lung cancer (NSCLC), levels of eIF4E are significantly increased compared with normal lung tissue. Here, we used an antisense oligonucleotide (ASO) to inhibit the expression of eIF4E in NSCLC cell lines. eIF4E levels were significantly reduced in a dose-dependent manner in NSCLC cells treated with eIF4E-specific ASO (4EASO) compared with control ASO. Treatment of NSCLC cells with the 4EASO resulted in decreased cap-dependent complex formation, decreased cell proliferation and increased sensitivity to gemcitabine. At the molecular level, repression of eIF4E with ASO resulted in decreased expression of the oncogenic proteins VEGF, c-Myc and osteopontin, whereas expression of β-actin was unaffected. Based on these findings, we conclude that eIF4E-silencing therapy alone or in conjunction with chemotherapy represents a promising approach deserving of further investigation in future NSCLC clinical trials.
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Thumma
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Jacobson
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Patel
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: B W
authors.initials: BW
authors.lastname: Konicek
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Franklin
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jay-Dixon
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sadiq
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: De
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Graff
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Kratzke
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D058990:Molecular Targeted Therapy / Q000379:methods*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D053495:Osteopontin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D016376:Oligonucleotides, Antisense; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D053495:Osteopontin; D000093542:Gemcitabine