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Cell growth potential drives ferroptosis susceptibility in rhabdomyosarcoma and myoblast cell lines

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

Ferroptosis is a programmed form of iron-dependent cell death caused by lipid hydroperoxide accumulation, which can be prevented by glutathione peroxidase 4 (GPx4) activity. Here we investigated the effects of ferroptosis inducers called erastin and RSL3, which act by glutathione depletion and GPx4 inactivation, respectively, on muscle-derived cell lines of embryonal and alveolar rhabdomyosarcoma (RMS), and mouse normal skeletal C2C12 myoblasts.

Methods

Myogenic lines were exposed to stepwise increasing concentrations of ferroptosis inducers either alone or in combination with iron supplementation, iron chelating agents (bathophenanthrolinedisulfonic acid, BPS), antioxidant molecules (glutathione, N-acetylcysteine), lipid peroxidation inhibitors (ferrostatin-1), and chemotherapeutic agents (doxorubicin and actinomycin D). Drug susceptibility was quantified by measuring cell viability, proliferation and differentiation via neutral red assay, crystal violet assay and Giemsa staining, respectively. The detection of lipid hydroperoxide and protein levels was performed by immunofluorescence and Western blot analysis, respectively.

Results

Erastin and RSL3 increased lipid hydroperoxide levels preferentially in the embryonal U57810 and myoblast C2C12 lines, leading to ferroptosis that was accentuated by iron supplementation or prevented by co-treatment with BPS, glutathione, N-acetylcysteine and ferrostatin-1. The inhibition of extracellular regulated kinases (ERK) pathway prevented ferroptosis in U57810 and C2C12 cells, whereas its increased activation in the embryonal RD cells mediated by caveolin-1 (Cav-1) overexpression led to augmented ferroptosis susceptibility. Finally, we observed the combination of erastin or RSL3 with chemotherapeutic doxorubicin and actinomycin D agents to be effective in increasing cell death in all RMS lines.

Conclusions

Erastin and RSL3 trigger ferroptosis in highly proliferating myogenic lines through a ERK pathway-dependent fashion.

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Acknowledgements

This work was supported by the University of Brescia (ex 60%) and Siderurgica Leonessa research funds to AF. We are grateful to Associazione Garda Vita for granting MA and Umberto Veronesi Foundation for granting FM with Post-doctoral Fellowship year-2018 Award.

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Authors and Affiliations

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

    Silvia Codenotti, Maura Poli, Michela Asperti, Daniela Zizioli & Alessandro Fanzani

  2. Division of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

    Francesco Marampon

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  1. Silvia Codenotti
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  2. Maura Poli
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  6. Alessandro Fanzani
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SC, MP, and AF planned experiments; SC, MA, and DZ performed experiments; SC, MP, FM, and AF analyzed data; AF wrote the paper.

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Correspondence to Alessandro Fanzani.

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Codenotti, S., Poli, M., Asperti, M. et al. Cell growth potential drives ferroptosis susceptibility in rhabdomyosarcoma and myoblast cell lines. J Cancer Res Clin Oncol 144, 1717–1730 (2018). https://doi.org/10.1007/s00432-018-2699-0

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