Identification of novel therapeutic targets in the secretome of ionizing radiation induced senescent tumor cells

Hyun Jung Hwang, Seung Hee Jung, Hyung Chul Lee, Na Kyung Han, In Hwa Bae, Minyoung Lee, Young Hoon Han, Young Sun Kang, Su Jae Lee, Heon Joo Park, Young-Gyu Ko, Jae Seon Lee

Research output: Contribution to journalArticle

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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 INK4/ARF locus and DNA damage. Senescence has been considered a tumorsuppressing 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 senescenceassociated 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 MCF10A 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 tubeformation activity. Since OPG markedly affected cell motility, we examined the effect of senescent conditioned media containing neutralizing OPG antibodies on migration and woundhealing activity. Our results demonstrated that IRinduced 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.

Original languageEnglish
Pages (from-to)841-850
Number of pages10
JournalOncology Reports
Volume35
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1

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Osteoprotegerin
Ionizing Radiation
Apolipoprotein E3
Tumor Microenvironment
Neoplasms
Therapeutics
Cytokines
Cell Movement
Telomere Shortening
Cell Aging
Human Umbilical Vein Endothelial Cells
MCF-7 Cells
Conditioned Culture Medium
Neutralizing Antibodies
Epigenomics
Wound Healing
DNA Damage
Proteins
Radiotherapy
Western Blotting

Keywords

  • Angiogenesis
  • Cytokine
  • Migration
  • Radiation
  • Senescent cancer cells
  • TNFRSR11B invasion
  • Wound healing

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hwang, H. J., Jung, S. H., Lee, H. C., Han, N. K., Bae, I. H., Lee, M., ... Lee, J. S. (2016). Identification of novel therapeutic targets in the secretome of ionizing radiation induced senescent tumor cells. Oncology Reports, 35(2), 841-850. https://doi.org/10.3892/or.2015.4473

Identification of novel therapeutic targets in the secretome of ionizing radiation induced senescent tumor cells. / Hwang, Hyun Jung; Jung, Seung Hee; Lee, Hyung Chul; Han, Na Kyung; Bae, In Hwa; Lee, Minyoung; Han, Young Hoon; Kang, Young Sun; Lee, Su Jae; Park, Heon Joo; Ko, Young-Gyu; Lee, Jae Seon.

In: Oncology Reports, Vol. 35, No. 2, 01.02.2016, p. 841-850.

Research output: Contribution to journalArticle

Hwang, HJ, Jung, SH, Lee, HC, Han, NK, Bae, IH, Lee, M, Han, YH, Kang, YS, Lee, SJ, Park, HJ, Ko, Y-G & Lee, JS 2016, 'Identification of novel therapeutic targets in the secretome of ionizing radiation induced senescent tumor cells', Oncology Reports, vol. 35, no. 2, pp. 841-850. https://doi.org/10.3892/or.2015.4473
Hwang, Hyun Jung ; Jung, Seung Hee ; Lee, Hyung Chul ; Han, Na Kyung ; Bae, In Hwa ; Lee, Minyoung ; Han, Young Hoon ; Kang, Young Sun ; Lee, Su Jae ; Park, Heon Joo ; Ko, Young-Gyu ; Lee, Jae Seon. / Identification of novel therapeutic targets in the secretome of ionizing radiation induced senescent tumor cells. In: Oncology Reports. 2016 ; Vol. 35, No. 2. pp. 841-850.
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