Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells.
The ability of tumour cells to resist apoptosis-inducing signals by cytotoxic T cells may decide the success or failure of tumour elimination. An important effector of apoptosis is the CD95/CD95 ligand system (APO-1/Fas) that mediates perforin-independent cytotoxic T-cell killing of tumour cells. We propose a new strategy by which tumour cells can resist CD95-induced apoptosis. We identified matrix metalloproteinase-7, MMP-7 (Martilysin), as the first physiologically relevant protease that can specifically cleave CD95. MMP-7 is of unique importance because it is produced by the tumour cells themselves at early stages of tumour development. Microsequencing of the positions in CD95 cleaved by MMP-7 revealed two sites in the N-terminal extracellular domain of CD95, important for preligand assembly of CD95. MMP-7 cleavage of CD95 results in reduced CD95 surface expression and decreased CD95-mediated apoptosis sensitivity of tumour cells. Treatment of MMP-7-positive HT-29 tumour cells with MMP-7-antisense oligonucleotides led to an increase in CD95-mediated apoptosis sensitivity. Finally, specific cytotoxic T-cell killing was reduced in the presence of MMP-7. Thus, MMP-7 expression in tumour cells may contribute to an apoptosis-resistant phenotype, which ultimately promotes immune escape. This activity may account for the well-established role of MMP-7 in early tumour development.
Strand
Susanne
S
I. Department of Internal Medicine, Johannes Gutenberg University, Obere Zahlbacherstr. 63, 55101 Mainz, Germany. sstrand@mail.uni-mainz.de
Vollmer
Petra
P
van den Abeelen
Lothar
L
Gottfried
Daniela
D
Alla
Vijay
V
Heid
Hans
H
Kuball
Jürgen
J
Theobald
Matthias
M
Galle
Peter R
PR
Strand
Dennis
D
D017209:Apoptosis / Q000502:physiology*; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D019014:fas Receptor; D020783:Matrix Metalloproteinase 7