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Hypertonicity primes malignant melanoma cells for apoptosis

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Abstract

The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na+ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy.

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Acknowledgements

ME is supported by Grants from Deutsche Forschungsgemeinschaft (DFG Grant EH 465/2-1), the Universitätsstiftung Helga und Erwin Hartl and the Medical Faculty of the University of Regensburg (ReForM-B-program).

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Authors and Affiliations

  1. Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany

    Diana Nicoleta Calance, Charlotte Steixner, Gertrud Knoll & Martin Ehrenschwender

  2. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany

    Stefanie Gross & Beatrice Schuler-Thurner

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  1. Diana Nicoleta Calance
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  6. Martin Ehrenschwender
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Contributions

ME designed experiments, analyzed data and wrote the paper; DNC, CS and GK performed experiments. BS-T and SG obtained informed consent from patients and established malignant melanoma cell lines.

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Correspondence to Martin Ehrenschwender.

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The authors declare that they have no conflict of interest.

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Calance, D.N., Steixner, C., Gross, S. et al. Hypertonicity primes malignant melanoma cells for apoptosis. Apoptosis 23, 201–209 (2018). https://doi.org/10.1007/s10495-018-1446-y

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