Invasion-associated MMP-2 and MMP-9 are up-regulated intracellularly in concert with apoptosis linked to melanoma cell detachment.
Matrix metalloproteinases, like MMP-2 and MMP-9 gelatinases, show multiple functions as extracellular/cell-surface enzymes, and are broadly recognised for their matrix-degrading ability and involvement in cell motility. Given that adherent cells have reduced attachment during migration and also detach from their substratum during apoptosis, we now investigated whether extracellular matrix-bound gelatinases and intracellular MMP-2 and MMP-9 are modified with progression of death-inducing stimuli. This report shows that melanoma cells undergoing death in response to 2-acetyl furanonaphtoquinone (FNQ) as evidenced by greater Annexin V binding, increased cytosolic expression of pro-MMP-2 and intracellular activation of particulate MMP-9. These changes were associated with early activation of a substrate-attached 40 kDa gelatinase reciprocal with changes in extracellular matrix-bound activated MMP-2. A subsequent activation of secreted MMP-9 and induction of apoptosis-associated fragmentation of poly ADP-Ribose polymerase (PARP) correlated with cell detachment. Our data suggests that intracellularly activated gelatinases may cleave survival-associated substrates other than gelatin that share the Gly-Leu/Iso-Pro like collagen-binding acetylcholinesterase, thereby linking them to apoptosis associated with cell detachment.
Pereira
Ana Maria Mendes
AM
Laboratory of Tumor Cell Biology, Centre for Microbiology and Cell Biology, IVIC, Apartado 21827, Caracas, 1020 A, Venezuela. mrieber@ivic.ve
Strasberg-Rieber
Mary
M
Rieber
Manuel
M
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009285:Naphthoquinones / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology; D015854:Up-Regulation; D014867:Water / Q000494:pharmacology
D017304:Annexin A5; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D014867:Water; D011065:Poly(ADP-ribose) Polymerases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9