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Salinomycin kills cancer stem cells by sequestering iron in lysosomes

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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Figure 1: Sal and AM5 alter the maintenance of CSCs independently of sodium transport.
Figure 2: Sal and AM5 sequester iron in lysosomes and trigger ferritin degradation in response to iron depletion.
Figure 3: Accumulation of iron in lysosomes promotes ROS production and lysosomal dysfunction.
Figure 4: Iron is involved in the maintenance of CSCs.

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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.

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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.

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Correspondence to Maryam Mehrpour or Raphaël Rodriguez.

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Mai, T., Hamaï, A., Hienzsch, A. et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nature Chem 9, 1025–1033 (2017). https://doi.org/10.1038/nchem.2778

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