title: Evaluation of premature senescence and senescence biomarkers in carcinoma cells and xenograft mice exposed to single or fractionated irradiation.
abstract: The purpose of the present study was to elucidate whether premature senescence contributes to the outcome of radiotherapy (RT) and to validate senescence biomarkers in vitro and in vivo. Cultured human cancer cell lines and xenografted mice were exposed to single (SR; 2, 6 or 12 Gy) or fractionated radiation (FR; 3 x 2 Gy or 6 x 2 Gy), and premature senescence was assessed using senescence-associated β-galactosidase (SA-β-Gal) activity, hypophosphorylation of pRb and p21 accumulation. A variety of senescence-associated biomarkers including cathepsin D (CD), the eukaryotic translation elongation factors eEF1A1, eEF1B2, decoy receptor 2 and Dec1 were further validated in vivo or in vitro. We demonstrated the beneficial tumor suppressive role of ionizing radiation (IR)-induced premature senescence in vitro and in vivo. FR inhibited tumor growth via induction of premature senescence as effectively as an equivalent SR dose (≥6 Gy). In addition, CD and eEF1 were valuable biomarkers of cellular senescence in either SR- or RF-exposed carcinoma cells or xenograft mice. Our results suggest that 2 Gy of a conventional RT regime could achieve a better clinical outcome if premature senescence could be increased through an improved understanding of its molecular action mechanism.
authors.affiliation: Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Bong Cho
authors.initials: BC
authors.lastname: Kim
authors.affiliation: Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Hyung Chul
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Kyoung-Ah
authors.initials: KA
authors.lastname: Kang
authors.affiliation: Research Center for Radio-senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Seungwoo
authors.initials: S
authors.lastname: Park
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Ji
authors.affiliation: School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Division of Life Sciences, Korea University, Seoul, Republic of Korea.
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Ko
authors.affiliation: Division of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000528:radiation effects*; D002277:Carcinoma / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D053319:Tumor Necrosis Factor Decoy Receptors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; C403671:DELEC1 protein, human; C094814:EEF1A1 protein, human; D020648:Peptide Elongation Factor 1; D016160:Retinoblastoma Protein; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D025521:Tumor Suppressor Proteins; D001616:beta-Galactosidase; D002402:Cathepsin D