title: Identification of novel therapeutic targets in the secretome of ionizing radiation‑induced senescent tumor cells.
abstract: Cellular senescence is a state of irreversible growth arrest that can be triggered by multiple mechanisms, including telomere shortening, the epigenetic derepression of the INK4α/ARF locus and DNA damage. Senescence has been considered a tumor‑suppressing mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells have deleterious effects on the tissue microenvironment. Some of these effects could be attributed to the senescence‑associated secretory phenotype that has the ability to promote tumor progression. However, secreted proteins from senescent tumor cells and their effects on the tumor microenvironment due to ionizing radiation (IR) exposure have not yet been fully elucidated. In the present study, we analyzed cytokines secreted from IR‑induced senescent MCF7 cells by using cytokine microarrays and confirmed by western blot analysis that increased secretion of osteoprotegerin (OPG), midkine (MDK) and apolipoprotein E3 (ApoE3) occurs in these cells. Invasive, migratory and wound‑healing activities were observed in MDA‑MB‑231 and MCF‑10A cells following treatment with recombinant human OPG, MDK and ApoE3 proteins. Additionally, tube‑formation activity was assessed in OPG‑, MDK‑ and ApoE3‑treated human umbilical vein endothelial cells (HUVECs). We found that OPG, MDK and ApoE3 affected cell motility and tube‑formation activity. Since OPG markedly affected cell motility, we examined the effect of senescent conditioned media containing neutralizing OPG antibodies on migration and wound‑healing activity. Our results demonstrated that IR‑induced senescent tumor cells influence the tumor microenvironment by increasing the production of cytokines, such as OPG, MDK and ApoE3. Furthermore, these data suggest that OPG is likely a promising target capable of reducing the deleterious effects on the tumor microenvironment during radiation therapy.
authors.affiliation: Department of Molecular Medicine and The Medical Research Center, Inha University College of Medicine, Incheon 22212, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Hwang
authors.affiliation: Department of Molecular Medicine and The Medical Research Center, Inha University College of Medicine, Incheon 22212, Republic of Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Department of Molecular Medicine and The Medical Research Center, Inha University College of Medicine, Incheon 22212, Republic of Korea.
authors.forename: Hyung Chul
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Research Institute of Radiological and Medical Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139‑706, Republic of Korea.
authors.forename: Na Kyung
authors.initials: NK
authors.lastname: Han
authors.affiliation: Research Institute of Radiological and Medical Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139‑706, Republic of Korea.
authors.forename: In Hwa
authors.initials: IH
authors.lastname: Bae
authors.affiliation: Research Institute of Radiological and Medical Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139‑706, Republic of Korea.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Research Institute of Radiological and Medical Sciences, Korea Institute of Radiological and Medical Sciences, Seoul 139‑706, Republic of Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Han
authors.affiliation: Department of Biomedical Science and Technology, College of Veterinary Medicine, Konkuk University, Seoul 143‑701, Republic of Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Kang
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133‑791, Republic of Korea.
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Microbiology and The Medical Research Center, Inha University College of Medicine, Incheon 22212, Republic of Korea.
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
authors.affiliation: School of Life Science and Biotechnology, Korea University, Seoul 136‑701, Republic of Korea.
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Ko
authors.affiliation: Department of Molecular Medicine and The Medical Research Center, Inha University College of Medicine, Incheon 22212, Republic of Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology* / Q000528:radiation effects*; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011839:Radiation, Ionizing; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D016207:Cytokines