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Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms

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Abstract

Fibroblast activation protein (FAP), an integral membrane serine protease, is found on fibro- and osteo-sarcoma and on myofibroblasts in epithelial carcinoma, but rarely on other adult tissue. FAP has been demonstrated to be an excellent target for tumor imaging in clinical trials, and antibodies and other FAP-targeting drugs are in development. Here we have shown that FAP overexpression increased the growth of HT1080 fibrosarcoma cells in vitro and in vivo, and found that the expression of FAP affects response to chemotherapy. When treated with doxorubicin, expression of FAP increased susceptibility to the drug. In spite of this, FAP-HT1080 cells had fewer markers of classical apoptosis than HT1080 cells and neither necrosis nor necroptosis were enhanced. However, levels of early mitochondrial and lysosomal membrane permeability markers were increased, and autophagy switched from a protective function in HT1080 cells to part of the cell death mechanism with FAP expression. Therefore, FAP may affect how the tumor responds to chemotherapeutic drugs overall, which should be considered in targeted drug development. The overexpression of FAP also alters cell signaling and responses to the environment in this cell line. This includes cell death mechanisms, changing the response of HT1080 cells to doxorubicin from classical apoptosis to an organelle membrane permeability-dependent form of cell death.

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Acknowledgments

This work was supported by the Austin Health Medical Research Foundation (SB), National Health and Medical Research Council Program Grant No. 487922 and Operational Infrastructure Support Program funding from the Victorian Government (all authors).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, 18 Frederick St, Dunedin, 9016, New Zealand

    Sarah K. Baird

  2. Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University, Melbourne, Australia

    Angela Rigopoulos, Diana Cao, Laura Allan, Fiona E. Scott & Andrew M. Scott

  3. Department of Oncology, University Hospital Basel, Basel, Switzerland

    Christoph Renner

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  1. Sarah K. Baird
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  2. Angela Rigopoulos
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  3. Diana Cao
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Correspondence to Sarah K. Baird.

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All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Austin Hospital Animal Ethics Committee.

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Baird, S.K., Rigopoulos, A., Cao, D. et al. Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms. Apoptosis 20, 1483–1498 (2015). https://doi.org/10.1007/s10495-015-1166-5

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  • DOI: https://doi.org/10.1007/s10495-015-1166-5

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