HL-60 LEUKEMIA-CELLS PRODUCE AN AUTOCATALYTICALLY TRUNCATED FORM OF MATRIX METALLOPROTEINASE-9 WITH IMPAIRED SENSITIVITY TO INHIBITION BY TISSUE INHIBITORS OF METALLOPROTEINASES

92-kDa type IV collagenase/gelatinase (matrix metalloproteinase-9; MMP -9; gelatinase B) expression and secretion has been shown to correlate with the invasive and metastatic potential of various malignant cells . MMP activity is tightly controlled by specific tissue inhibitors of metalloproteinases (TIMPs). We found the leukemic cell line HL-60 cons titutively to release a 94-kDa gelatinase which we identified as MMP-9 shortened by nine amino acids at its N-terminal end. An additional ge latinolytic activity was present in small amounts and identified as a 63-kDa fragment of MMP-9 generated by autocatalytical processing. Both enzymes were identical regarding their N-terminus, indicating C-termi nal truncation for the former. Incubation of cells with phorbol ester resulted in elevated amounts of both enzymes in conditioned media and in the secretion of TIMP-1. Both gelatinases were shown to he activate d by trypsin and organomercurials and to possess similar activities to wards various substrates. However, the 63-kDa enzyme differed from the 94-kDa enzyme in a significantly reduced inhibition by recombinant TI MP-1 and TIMP-2. Thus, the 63-kDa fragment of MMP-9 once activated may escape the regulatory influence of its specific inhibitors and may th ereby promote matrix degradation during invasion of leukemic cells.