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NRF2 orchestrates the redox regulation induced by radiation therapy, sustaining embryonal and alveolar rhabdomyosarcoma cells radioresistance

  • Original Article – Cancer Research
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Abstract

Purpose

Tumor cells generally exhibit higher levels of reactive oxygen species (ROS), however, when stressed, tumor cells can undergo a process of ‘Redox Resetting’ to acquire a new redox balance with stronger antioxidant systems that enable cancer cells to become resistant to radiation therapy (RT). Here, we describe how RT affects the oxidant/antioxidant balance in human embryonal (RD) and alveolar (RH30) rhabdomyosarcoma (RMS) cell lines, investigating on the molecular mechanisms involved.

Methods

Radiations were delivered using an x-6 MV photon linear accelerator and their effects were assessed by vitality and clonogenic assays. The expression of specific antioxidant-enzymes, such as Superoxide Dismutases (SODs), Catalase (CAT) and Glutathione Peroxidases 4 (GPx4), miRNAs (miR-22, -126, -210, -375, -146a, -34a) and the transcription factor NRF2 was analyzed by quantitative polymerase chain reaction (q-PCR) and western blotting. RNA interference experiments were performed to evaluate the role of NRF2.

Results

Doses of RT higher than 2 Gy significantly affected RMS clonogenic ability by increasing ROS production. RMS rapidly and efficiently brought back ROS levels by up-regulating the gene expression of antioxidant enzymes, miRNAs as well as of NRF2. Silencing of NRF2 restrained the RMS ability to counteract RT-induced ROS accumulation, antioxidant enzyme and miRNA expression and was able to increase the abundance of γ-H2AX, a biomarker of DNA damage, in RT-treated cells.

Conclusions

Taken together, our data suggest the strategic role of oxidant/antioxidant balance in restraining the therapeutic efficiency of RT in RMS treatment and identify NRF2 as a new potential molecular target whose inhibition might represent a novel radiosensitizing therapeutic strategy for RMS clinical management.

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Acknowledgements

We are grateful to the Umberto Veronesi Foundation for awarding a post-doctoral fellowship to Francesco Marampon for the year 2018 and “FIVA Confcommercio” for supporting part of our work.

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Author notes

  1. Francesco Marampon, Silvia Codenotti, Sara Cheleschi and Paolo Tini equally contributed.

Authors and Affiliations

  1. Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy

    Francesco Marampon, Daniela Musio, Francesca De Felice, Carlo Dominici & Vincenzo Tombolini

  2. Division of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Silvia Codenotti & Alessandro Fanzani

  3. Department of Pediatrics, “Sapienza” University of Rome, Rome, Italy

    Francesca Megiorni & Simona Camero

  4. Multi-Factorial Disease and Complex Phenotype Research Area, Bambino Gesù Children’s Hospital, IRCCS, Viale di San Paolo 15, 00146, Rome, Italy

    Andrea Del Fattore

  5. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, Coppito 2, 67100, L’Aquila, Italy

    Giovanni Luca Gravina & Claudio Festuccia

  6. Unit of Radiation Therapy, Ospedale del Mare, Naples, Italy

    Valerio Nardone

  7. Azienda Ospedaliera Universitaria Senese, Siena, Italy

    Anna Natalizia Santoro & Luigi Pirtoli

  8. Unit of Radiation Oncology, Azienda Ospedaliera Universitaria Senese, Siena, Italy

    Luigi Pirtoli & Paolo Tini

  9. Istituto Toscano Tumori, Florence, Italy

    Luigi Pirtoli & Paolo Tini

  10. Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy

    Luigi Pirtoli

  11. Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA

    Luigi Pirtoli & Paolo Tini

  12. Department of Medicine, Surgery and Neuroscience, Rheumatology Unit, University of Siena, Policlinico Le Scotte, Siena, Italy

    Luigi Pirtoli & Sara Cheleschi

  13. Sbarro Health Research Organization, Temple University, Philadelphia, PA, USA

    Antonella Fioravanti & Paolo Tini

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  1. Francesco Marampon
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  2. Silvia Codenotti
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  3. Francesca Megiorni
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Contributions

FMa, SC, FMe and ADF planned experiments; SC, GLG, CF, DM, FDF, VN and ANS performed experiments; CD, LP, AF VT and AF analyze data; SC and PT wrote the paper.

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Correspondence to Francesco Marampon.

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Marampon, F., Codenotti, S., Megiorni, F. et al. NRF2 orchestrates the redox regulation induced by radiation therapy, sustaining embryonal and alveolar rhabdomyosarcoma cells radioresistance. J Cancer Res Clin Oncol 145, 881–893 (2019). https://doi.org/10.1007/s00432-019-02851-0

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