title: Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity.
abstract: The radiation stress induces cytotoxic responses of cell death as well as cytoprotective responses of cell survival. Understanding exact cellular mechanism and signal transduction pathways is important in improving cancer radiotherapy. Increasing evidence suggests that cyclic AMP response element binding protein (CREB)/activating transcription factor (ATF) family proteins act as a survival factor and a signaling molecule in response to stress. We postulated that CREB inhibition via CRE decoy oligonucleotide increases tumor cell sensitization to γ-irradiation-induced cytotoxic stress. In the present study, we demonstrate that CREB phosphorylation and CREB DNA-protein complex formation increased in time- and radiation dose-dependent manners, while there was no significant change in total protein level of CREB. In addition, CREB was phosphorylated in response to γ-irradiation through p38 MAPK pathway. Further investigation revealed that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radiosensitivity of multiple human cancer cell lines including TP53- and/or RB-mutated cells with minimal effects on normal cells. We also demonstrate that tumor cells ectopically expressing dominant negative mutant CREB (KCREB) and the cells treated with p38 MAPK inhibitors were more sensitive to γ-irradiation than wild type parental cells or control-treated cells. Taken together, we conclude that CREB protects tumor cells from γ-irradiation, and combination of CREB inhibition plus ionizing radiation will be a promising radiotherapeutic approach.
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea; The BK21 Plus Program for Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea; Department of Medicine and Center for Bone Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: serkin@korea.edu.
authors.forename: Serk In
authors.initials: SI
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea; Laboratory of Obesity and Aging Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Junghan
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Sohn
authors.affiliation: Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea. Electronic address: parkyg@korea.ac.kr.
authors.forename: Yun Gyu
authors.initials: YG
authors.lastname: Park
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D005720:Gamma Rays / Q000627:therapeutic use*; D006801:Humans; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy*; D009841:Oligonucleotides / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D051696:Activating Transcription Factors; D009841:Oligonucleotides; D051786:Cyclic AMP Response Element Modulator
keywords: Cyclic AMP response element; Decoy; Radiosensitization; p38 MAPK; γ-Irradiation