Calmodulin antagonists increase the expression of membrane‐type‐1 matrix metalloproteinase in human uterine cervical fibroblasts

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Abstract
The treatment of human uterine cervical fibroblasts with concanavalin A (ConA), or a specific calmodulin antagonist, N‐(6‐aminohexyl)‐5‐chloro‐1‐naphthalenesulfonamide (W‐7) or trifluoperazine resulted in accumulation of an active form of matrix metalloproteinase 2 (MMP‐2, gelatinase A). In contrast, N‐(6‐aminohexyl)‐1‐naphthalenesulfonamide (W‐5), a weaker antagonist of calmodulin, did not modulate the activation of proMMP‐2. The activation of proMMP‐2 was confirmed by the enhanced activity on gelatin and the conversion of proMMP‐2 to a 62‐kDa form by zymography and western blotting. The plasma membrane, but not the conditioned medium, of the W‐7‐ or trifluoperazine‐treated cells activated proMMP‐2; this activation was blocked by membrane‐type‐1 MMP (MT1‐MMP) antibody and EDTA. The plasma membrane from trifluoperazine‐ or ConA‐treated cells contained MT1‐MMP and tissue inhibitor of metalloproteinases 2. Both trifluoperazine treatment and ConA treatment increased the steady‐state levels of MT1‐MMP mRNA and proMMP‐2 mRNA. These results, together with our previous observations on the production of proMMP‐1 (interstitial procollagenase) and proMMP‐3 (prostromelysin 1) [Ito, A., Sato, T., Ojima, Y., Chen, L.‐C., Nagase, H. & Mori, Y. (1991) J. Biol. Chem. 266, 13 598−13 601], suggest that calmodulin negatively regulates the matrix turnover by suppressing the production of a number of proMMPs including proMMP‐1, proMMP‐3 and MT1‐MMP, and the activation of proMMP‐2 in human uterine cervical fibroblasts.

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