© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 19, 1678-1684,
October 6, 1999
© 1999 Oxford University Press
REPORT |
Fas-Mediated Apoptosis in Ewing's Sarcoma Cell Lines by Metalloproteinase Inhibitors
Affiliation of authors: Laboratory of Pathology, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Correspondence to present address: Nicholas Mitsiades, M.D., Massachusetts General Hospital, Molecular Pathology Unit, Molecular Pathology Unit, 149 13th St., 7th Floor, Charlestown, MA 02129 (e-mail: mitsiade{at}helix.mgh.harvard.edu).
BACKGROUND: Fas ligand (FasL) is a transmembrane protein that induces apoptosis (programmed cell death) in susceptible cells by interacting with its receptor, Fas. Transmembrane FasL is cleaved by a metalloproteinase enzyme into a soluble form that is released into the extracellular medium. Tumors of the Ewing's sarcoma family express functional transmembrane FasL and release soluble FasL. This cleavage is inhibited by a matrix metalloproteinase inhibitor (MMPI). We therefore hypothesized that MMPIs can lead to apoptosis of tumor cells by inducing accumulation of transmembrane FasL. METHODS: Ewing's sarcoma and neuroblastoma cell lines were treated with two synthetic MMPIs (BB-3103 and A-151011) and examined for apoptosis and expression of FasL and Fas. RESULTS: Although MMPIs increase levels of FasL and Fas proteins on the surface of all tumor cells studied, they induced apoptosis in Fas-sensitive but not in Fas-resistant cell lines; the induction of apoptosis was inhibited by a Fas-neutralizing antibody. The increase in protein expression was not associated with enhanced transcription. Treatment with an MMPI sensitized the Ewing's sarcoma cells to Fas-activating antibody and to doxorubicin-induced apoptosis. CONCLUSIONS: MMPIs cause accumulation of transmembrane FasL by inhibiting its cleavage, accumulation of Fas (probably secondarily to FasL cleavage inhibition), and decreased levels of soluble FasL. These effects lead to apoptosis in Fas-sensitive cell lines. The observed cooperative action of MMPIs and doxorubicin suggests a possible role of MMPIs in combination treatments with standard apoptosis-inducing chemotherapeutic agents.
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