Matrix Metalloproteinases Are Involved in Both Type I (Apoptos...

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.