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Complex Regulation of Membrane-Type Matrix Metalloproteinase Expression and Matrix Metalloproteinase-2 Activation by Concanavalin A in MDA-MB-231 Human Breast Cancer Cells¹

Departments of Cell Biology [M. Y., E. W. T.] and Orthopedic Surgery [E. W. T.] and Lombardi Cancer Center [M. Y., E. W. T.], Georgetown University Medical Center, Washington DC, 20007, and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920, Japan [H. S., M. S.]

Matrix Metalloproteinase-2 (MMP-2) is secreted as a zymogen, the activation of which has been associated with metastatic progression in human breast cancer (HBC). Concanavalin A (Con A) has been found to induce activation of MMP-2 in invasive HBC cell lines. Con A effects on the expression of mRNA for membrane-type matrix metalloproteinase (MT-MMP), a newly described cell surface-associated MMP, showed a close temporal correlation with induction of MMP-2 activation. It is surprising that MT-MMP mRNA is constitutively present in the uninduced MDA-MB-231 cell, despite a lack of MMP-2 activation. We have used actinomycin D to demonstrate a partial requirement for de novo gene expression in the induction of MMP-2 activation by Con A in MDA-MB-231 HBC cells. Furthermore, this transcriptional response to Con A appeared to require the continued presence of Con A for its manifestation. The nontranscriptional component of the Con A induction manifests rapidly, is quite substantial, and persists strongly despite actinomycin D abrogation of both constitutive and Con A-induced MT-MMP. Cycloheximide analyses suggest that protein synthesis may be involved in this rapid transcription-independent response. These studies suggest that Con A induces MMP-2-activation in part by up-regulation of MT-MMP expression but has a more complicated mode of action, involving additional nontranscriptional effects, which apparently require protein synthesis.

¹ This work was supported in part by NIH Grant CA61344.

² To whom requests for reprints should be addressed, at Room W416 NRB, Lombardi Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, N.W., Washington DC, 20007.

Received 3/14/95. Accepted 6/16/95.

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