Article

Salinomycin kills cancer stem cells by sequestering iron in lysosomes

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Abstract

Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo, by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells.

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Acknowledgements

We thank the CNRS, INSERM and SATT IDF Innov for generous funding. Research in the R.R. laboratory is supported by the European Research Council (grant number 647973), Fondation pour la Recherche Médicale (grant reference AJE20141031486), Emergence Ville de Paris and Ligue Contre le Cancer. A.Ha. is funded by the Fondation de France. We acknowledge the PICT-IBiSA@Pasteur Imaging Facility of Institut Curie, member of the France-BioImaging national research infrastructure. We thank P. Le Bacon for assistance with high-resolution microscopy, J.-F. Gallard, N. Birlirakis and C. Gaillet for assistance with NMR spectroscopy and J. Poupon for electrothermal atomic absorption spectrometry experiments. We thank A. Puisieux for providing us with HMLER cells and V. Mitz for mammary tissues obtained from reduction mammoplasty.

Author information

Author notes

    • Trang Thi Mai
    • , Ahmed Hamaï
    •  & Antje Hienzsch

    These authors contributed equally to this work.

Affiliations

  1. Institut Curie, PSL Research University, Chemical Cell Biology Group, 26 rue d'Ulm, 75248 Paris Cedex 05, France

    • Trang Thi Mai
    • , Tatiana Cañeque
    • , Sebastian Müller
    • , Verónica Acevedo
    •  & Raphaël Rodriguez
  2. CNRS UMR3666, 75005 Paris, France

    • Trang Thi Mai
    • , Tatiana Cañeque
    • , Sebastian Müller
    • , Verónica Acevedo
    •  & Raphaël Rodriguez
  3. INSERM U1143, 75005 Paris, France

    • Trang Thi Mai
    • , Tatiana Cañeque
    • , Sebastian Müller
    • , Verónica Acevedo
    •  & Raphaël Rodriguez
  4. Institut de Chimie des Substances Naturelles, UPR2301, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France

    • Trang Thi Mai
    • , Antje Hienzsch
    • , Tatiana Cañeque
    •  & Raphaël Rodriguez
  5. Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR8253, Université Paris Descartes-Sorbonne Paris Cité, 14 rue Maria Helena Vieira Da Silva, 75993 Paris Cedex 14, France

    • Ahmed Hamaï
    • , Christine Leroy
    • , Amandine David
    • , Patrice Codogno
    •  & Maryam Mehrpour
  6. ABX advanced biochemical compounds, Heinrich-Glaeser-Str. 10-14, D-01454 Radeberg, Germany

    • Antje Hienzsch
  7. Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée ‘Ligue contre le cancer’, 13009 Marseille, France

    • Julien Wicinski
    • , Olivier Cabaud
    • , Christophe Ginestier
    • , Daniel Birnbaum
    •  & Emmanuelle Charafe-Jauffret
  8. Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan

    • Akihide Ryo

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Contributions

R.R. conceptualized the study and designed ironomycin. R.R., T.T.M., M.M., A.Ha. and P.C. designed the experiments and analysed the data. T.T.M., A.Hi., A.Ha. and M.M. performed the experiments unless stated otherwise. A.Hi. and T.C. synthesized Sal derivatives and performed NMR experiments. J.W., O.C., C.G., D.B. and E.C.-J. provided PDX data. A.Ha., C.L. and A.D. provided MCF-7 tumour data. S.M. and V.A. provided assistance with cell imaging. A.R. provided iCSCL-10A2 cells. R.R. wrote the manuscript with contributions from T.C., S.M., A.Hi., A.Ha. and M.M.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Maryam Mehrpour or Raphaël Rodriguez.

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