The effects of
sodium phenylacetate (NaPa), an antitumoral molecule, on
cell death and
matrix metalloproteinase (MMP) activities and synthesis were investigated in two
metastatic breast tumour cell lines, MDA-MB-231 and MDA-MB-435, cultured on three-dimensional
type I collagen gels (3-D cultures). In both
cell lines, NaPa inhibited
cell proliferation and induced
apoptotic cell death as measured by
TUNEL assay, with an IC(30) of 20 mM and 10 mM for MDA-MB-231 and MDA-MB-435 cells, respectively. In MDA-MB-231 cells, NaPa also induced (i) an autophagic process evidenced by the appearance of autophagic
vacuoles and an increased
phosphatase acid activity, (ii) the formation of
pseudopodia and (iii) an increase in
MMP-1 and MMP-9
secretion without affecting
MT1-MMP. In NaPa-treated MDA-MB-435 cells, no autophagic
vacuoles were formed but
F-actin depolymerisation was observed.
MMP-1, MMP-9 and
MT1-MMP levels were strongly enhanced in these cells but MMPs were not
secreted and accumulated intracellularly. When
breast cancer cells were treated with NaPa in the presence of an MMP inhibitor (GM6001),
apoptotic cell death decreased and the induction of autophagic
vacuoles in MDA-MB-231 cells was inhibited. Taken together, these data suggest that MMPs are involved in the autophagic
cell death and/or
apoptosis of
breast tumour cells.
