Constitutive production of 92-kDa gelatinase B can be suppressed by alterations in cell shape.

We have examined the effect that cell shape has on production of the 92-kDa gelatinase B, an enzyme of the matrix metalloproteinase family thought to contribute to the invasiveness of both normal and malignant cells. Using the agent poly(HEMA) and a human melanoma cell line that constitutively produces both the 72- and 92-kDa gelatinases, we have found that alteration in cell shape, that is, a change in cell "roundness," resulted in a specific loss of the constitutive production of the 92-kDa gelatinase B. To examine this phenomenon further, cells were treated with an inhibitor of actin polymerization, cytochalasin D. This treatment also resulted in a loss of 92-kDa gelatinase B production, provided the cells were treated with drug from the out-set of the experiment. If the cells were allowed to attach and spread prior to drug exposure, no loss of 92-kDa gelatinase B production was observed. Similar to the poly (HEMA) results, cytochalasin D had little effect on production of the 72-kDa gelatinase A. Treatment with the tubulin polymerization inhibitor colchicine had no effect on 92-kDa gelatinase B production, nor did growth of the cells as three-dimensional tumor spheroids, although an alteration in cell morphology was observed in both instances. This phenomenon was studied in another system, namely, HL-60 cells, which were induced to differentiate into macrophage-like cells in response to TPA treatment and consequently produce the 92-kDa gelatinase B. HL-60 cells treated with TPA and cytochalasin D failed to produce the 92-kDa gelatinase B. These results suggest that the 92-kDa gelatinase B can be regulated by alterations in cell shape but more specifically, by alterations in the organization of the actin cytoskeleton. Furthermore, the mechanism responsible for cell shape/actin cytoskeletal down-regulation of the 92-kDa gelatinase B may be common to many cell types competent to produce this enzymatic activity.