title: IL-6 signaling promotes DNA repair and prevents apoptosis in CD133+ stem-like cells of lung cancer after radiation.
abstract: Local tumor control by standard fractionated radiotherapy (RT) remains poor because of tumor resistance to radiation (radioresistance). It has been suggested that cancer stem cells (CSCs) are more radioresistant than non-CSCs. In previous studies, we have shown IL-6 promotes self-renewal of CD133+ CSC-like cells. In this study, we investigated whether IL-6 plays roles not only in promoting self-renewal of CD133+ cells after radiation, but also in conferring radioresistance of CD133+ cells in NSCLC.
  
  
  
  To compare radiation sensitivity of CSCs and non-CSCs, CD133+ CSC-like and CD133- cell populations were isolated from two NSCLC cell lines, A549 and H157, by immunomagnetic separation and their sensitivities to ionizing radiation were investigated using the clonogenic survival assay. To further study the IL-6 effect on the radiosensitivity of CD133+ CSC-like cells, CD133+ cells were isolated from A549IL-6si/sc and H157IL-6si/sc cells whose intracellular IL-6 levels were manipulated via the lentiviral transduction with IL-6siRNA. Post-irradiation DNA damage was analyzed by γ-H2AX staining and Comet assay. Molecular mechanisms by which IL-6 regulates the molecules associated with DNA repair and anti-apoptosis after radiation were analyzed by Western blot and immunofluoresecence (IF) staining analyses.
  
  
  
  NSCLC CD133+ CSC-like cells were enriched upon radiation. Survival of NSCLC CD133+ cells after radiation was higher than that of CD133- cells. Survival of IL-6 expressing NSC LC CD133+ cells (sc) was higher than that of IL-6 knocked-down cells (IL-6si) after radiation. IL-6 played a role in protecting NSCLC CD133+ cells from radiation-induced DNA damage and apoptosis.
  
  
  
  IL-6 signaling promotes DNA repair while protecting CD133+ CSC-like cells from apoptotic death after radiation for lung cancer. A combined therapy of radiation and agents that inhibit IL-6 signaling (or its downstream signaling) is suggested to reduce CSC-mediated radioresistance in lung cancer.
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. yuhchyau_chen@urmc.rochester.edu.
authors.forename: Yuhchyau
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. fuquan_zhang@urmc.rochester.edu.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. ying_tsai@urmc.rochester.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tsai
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. xiadong_yang@urmc.rochester.edu.
authors.forename: Xiadong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. li_yang@urmc.rochester.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. shanzhou_duan@urmc.rochester.edu.
authors.forename: Shanzhou
authors.initials: S
authors.lastname: Duan
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. xin_wang@urmc.rochester.edu.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. peter_keng@urmc.rochester.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Keng
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY, 14642, USA. soook_Lee@urmc.rochester.edu.
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D020552:Comet Assay; D004260:DNA Repair / Q000502:physiology* / Q000528:radiation effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D010455:Peptides / Q000378:metabolism; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects*; D014161:Transduction, Genetic
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C508600:IL6 protein, human; D015850:Interleukin-6; C000606023:PROM1 protein, human; D010455:Peptides; D034741:RNA, Small Interfering