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

Apoptosis 2015 Nov;20(11):1483-98

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

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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http://link.springer.com/10.1007/s10495-015-1166-5
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http://dx.doi.org/10.1007/s10495-015-1166-5DOI Listing
November 2015
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References

(Supplied by CrossRef)

JE Park et al.
J Biol Chem 1999

WJ Rettig et al.
Proc Natl Acad Sci USA 1988

P Garin-Chesa et al.
Proc Natl Acad Sci USA 1990

O Dohi et al.
Histopathology 2009

S Bauer et al.
Arthritis Res Ther 2006

MT Levy et al.
Liver 2002

AM Scott et al.
Clin Cancer Res 2003

RD Hofheinz et al.
Onkologie 2003

K Narra et al.
Cancer Biol Ther 2007

RM Eager et al.
Clin Oncol (R Coll Radiol) 2009

RM Eager et al.
BMC Cancer 2009

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