Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms.
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.
Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, 18 Frederick St, Dunedin, 9016, New Zealand. s.baird@otago.ac.nz.
Sarah K
SK
Baird
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University, Melbourne, Australia.
Angela
A
Rigopoulos
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University, Melbourne, Australia.
Diana
D
Cao
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University, Melbourne, Australia.
Laura
L
Allan
Department of Oncology, University Hospital Basel, Basel, Switzerland.
Christoph
C
Renner
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University, Melbourne, Australia.
Fiona E
FE
Scott
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University, Melbourne, Australia.
Andrew M
AM
Scott
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D010450:Endopeptidases; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000099167:Fibroblast Activation Protein Alpha
D000970:Antineoplastic Agents; D004317:Doxorubicin; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
Apoptosis; Doxorubicin; Necrosis; Proliferation; Stroma