Open Access

Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species

  • Authors:
    • Ai Nakaoka
    • Makiko Nakahana
    • Sachiko Inubushi
    • Hiroaki Akasaka
    • Mohammed Salah
    • Yoshiko Fujita
    • Hikaru Kubota
    • Mennaallah Hassan
    • Ryo Nishikawa
    • Naritoshi Mukumoto
    • Takeaki Ishihara
    • Daisuke Miyawaki
    • Takashi Sasayama
    • Ryohei Sasaki
  • View Affiliations

  • Published online on: February 2, 2021     https://doi.org/10.3892/or.2021.7964
  • Article Number: 13
  • Copyright: © Nakaoka et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The precise mechanism of intercellular communication between cancer cells following radiation exposure is unclear. Exosomes are membrane‑enclosed small vesicles comprising lipid bilayers and are mediators of intercellular communication that transport a variety of intracellular components, including microRNAs (miRNAs or miRs). The present study aimed to identify novel roles of exosomes released from irradiated cells to neighboring cancer cells. In order to confirm the presence of exosomes in the human pancreatic cancer cell line MIAPaCa‑2, ultracentrifugation was performed followed by transmission electron microscopy and nanoparticle tracking analysis (NanoSight) using the exosome‑specific surface markers CD9 and CD63. Subsequent endocytosis of exosomes was confirmed by fluorescent microscopy. Cell survival following irradiation and the addition of exosomes was evaluated by colony forming assay. Expression levels of miRNAs in exosomes were then quantified by microarray analysis, while protein expression levels of Cu/Zn‑ and Mn‑superoxide dismutase (SOD1 and 2, respectively) enzymes in MIAPaCa‑2 cells were evaluated by western blotting. Results showed that the uptake of irradiated exosomes was significantly higher than that of non‑irradiated exosomes. Notably, irradiated exosomes induced higher intracellular levels of reactive oxygen species (ROS) and a higher frequency of DNA damage in MIAPaCa‑2 cells, as determined by fluorescent microscopy and immunocytochemistry, respectively. Moreover, six up‑ and five downregulated miRNAs were identified in 5 and 8 Gy‑irradiated cells using miRNA microarray analyses. Further analysis using miRNA mimics and reverse transcription‑quantitative PCR identified miR‑6823‑5p as a potential candidate to inhibit SOD1, leading to increased intracellular ROS levels and DNA damage. To the best of our knowledge, the present study is the first to demonstrate that irradiated exosomes enhance the radiation effect via increasing intracellular ROS levels in cancer cells. This contributes to improved understanding of the bystander effect of neighboring cancer cells.
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April-2021
Volume 45 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Nakaoka A, Nakahana M, Inubushi S, Akasaka H, Salah M, Fujita Y, Kubota H, Hassan M, Nishikawa R, Mukumoto N, Mukumoto N, et al: Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species. Oncol Rep 45: 13, 2021
APA
Nakaoka, A., Nakahana, M., Inubushi, S., Akasaka, H., Salah, M., Fujita, Y. ... Sasaki, R. (2021). Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species. Oncology Reports, 45, 13. https://doi.org/10.3892/or.2021.7964
MLA
Nakaoka, A., Nakahana, M., Inubushi, S., Akasaka, H., Salah, M., Fujita, Y., Kubota, H., Hassan, M., Nishikawa, R., Mukumoto, N., Ishihara, T., Miyawaki, D., Sasayama, T., Sasaki, R."Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species". Oncology Reports 45.4 (2021): 13.
Chicago
Nakaoka, A., Nakahana, M., Inubushi, S., Akasaka, H., Salah, M., Fujita, Y., Kubota, H., Hassan, M., Nishikawa, R., Mukumoto, N., Ishihara, T., Miyawaki, D., Sasayama, T., Sasaki, R."Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species". Oncology Reports 45, no. 4 (2021): 13. https://doi.org/10.3892/or.2021.7964