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Stat3 controls lysosomal-mediated cell death in vivo

Nature Cell Biology volume 13, pages 303–309 (2011)Cite this article

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Abstract

It is well established that lysosomes play an active role during the execution of cell death1. A range of stimuli can lead to lysosomal membrane permeabilization (LMP), thus inducing programmed cell death without involvement of the classical apoptotic programme2,3. However, these lysosomal pathways of cell death have mostly been described in vitro or under pathological conditions4,5,6,7. Here we show that the physiological process of post-lactational regression of the mammary gland is accomplished through a non-classical, lysosomal-mediated pathway of cell death. We found that, during involution, lysosomes in the mammary epithelium undergo widespread LMP. Furthermore, although cell death through LMP is independent of executioner caspases 3, 6 and 7, it requires Stat3, which upregulates the expression of lysosomal proteases cathepsin B and L, while downregulating their endogenous inhibitor Spi2A (ref. 8). Our findings report a previously unknown, Stat3-regulated lysosomal-mediated pathway of cell death under physiological circumstances. We anticipate that these findings will be of major importance in the design of treatments for cancers such as breast, colon and liver, where cathepsins and Stat3 are commonly overexpressed and/or hyperactivated respectively1,9,10.

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Figure 1: Characteristics of physiological cell death in mammary gland involution.
Figure 2: Cell death in early involution is independent of executioner caspases.
Figure 3: Mammary lysosomes become leaky during involution.
Figure 4: Stat3 regulates cathepsin B and L expression.
Figure 5: Inhibition of cytosolic cathepsin activity prevents Stat3-mediated cell death.

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Acknowledgements

We thank J. Skepper for help with the electron microscopy and B. Potter for histological preparations. We thank also P. Came for the TUNEL data and W. Khaled for discussions. This work has been supported by a PhD studentship from the Pathology Department, University of Cambridge (P.A.K.), Breast Cancer Campaign PhD studentship (A.D.S. and W.L.), Italian Cancer Research Association (V.P.) and Biotechnology and Biological Sciences Research Council grant no. BB/C006836/1 (R.W.E.C. and N.O.).

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Authors and Affiliations

  1. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK

    Peter A. Kreuzaler, Anna D. Staniszewska, Wenjing Li, Blandine Kedjouar & Christine J. Watson

  2. School of Biosciences, University of Cardiff, Cardiff CF10 3US, UK

    Nader Omidvar & Richard W. E. Clarkson

  3. University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, USA

    James Turkson

  4. Department of Genetics, The Molecular Biotechnology Center (MBC), Biology and Biochemistry, University of Turin, 10126 Turin, Italy

    Valeria Poli

  5. Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    Richard A. Flavell

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Contributions

P.A.K. carried out project design and all experiments, except those stated separately and wrote the manuscript; A.D.S. designed and carried out the in vitro studies; W.L. carried out studies on caspase-knockout mice; N.O. and R.W.E.C. generated the p35 transgenic mouse and provided data; B.K. carried out caspase studies; J.T. provided Stat3 inhibitor; V.P. provided Stat3fl/fl mice; R.A.F. provided all caspase-knockout mice; C.J.W. carried out project design and wrote the manuscript.

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Correspondence to Christine J. Watson.

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Kreuzaler, P., Staniszewska, A., Li, W. et al. Stat3 controls lysosomal-mediated cell death in vivo. Nat Cell Biol 13, 303–309 (2011). https://doi.org/10.1038/ncb2171

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