FAPalpha, a surface peptidase expressed during wound healing, is a tumor suppressor.
Fibroblast activation protein-alpha (FAP) is a cell surface serine protease expressed at sites of tissue remodeling in embryonic development. FAP is not expressed by mature somatic tissues except activated melanocytes and fibroblasts in wound healing or tumor stroma. FAP expression is specifically silenced in proliferating melanocytic cells during malignant transformation. To study the role of FAP as a tumor suppressor, the gene for mouse fap was cloned and mutated at the catalytic domain (FAP serine mutant, FSM). We found that expression of FAP or FSM at physiologic levels in mouse melanoma cells abrogated tumorigenicity. Remarkably, the mutant form FSM lacking specific serine protease activity was a more potent tumor suppressor. Tumor rejection was not due to adaptive immune responses because RAG1-/- mice challenged with melanoma cells expressing either FAP or FSM were not tumorigenic. In in vitro assays, FAP or FSM expression restored contact inhibition, led to cell cycle arrest at G0/G1 phase, and increased susceptibility to stress-induced apoptosis. Cell death in FAP+ or FSM+ melanoma cells was readily triggered by depletion of survival factors from the media, leading to subsequent activation of caspases via the intrinsic pathway. These results show that expression of FAP is a tumor suppressor that abrogates tumorigenicity through regulation of cell growth and survival.
Ramirez-Montagut
Teresa
T
Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center and Weill Graduate School of Medical Sciences of Cornell University, 1275 York Avenue, New York, NY 10021, USA.
Blachere
Nathalie E
NE
Sviderskaya
Elena V
EV
Bennett
Dorothy C
DC
Rettig
Wolfgang J
WJ
Garin-Chesa
Pilar
P
Houghton
Alan N
AN
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D003260:Contact Inhibition / Q000235:genetics / Q000502:physiology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D012694:Serine / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics; D000099167:Fibroblast Activation Protein Alpha
D018819:Dipeptidyl Peptidase 4; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012694:Serine; D012697:Serine Endopeptidases; D025521:Tumor Suppressor Proteins; D000099167:Fibroblast Activation Protein Alpha