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.