Dimeric procyanidins attenuate matrix metalloproteinase-2 activity and suppress colorectal cancer cell invasion.

Abstract

Matrix metalloproteinase-2 (MMP-2) is a key extracellular protease involved in extracellular matrix degradation and colorectal cancer (CRC) cell invasion. Although dimeric procyanidins (PCA) epicatechin gallate (ECG) dimer and epigallocatechin gallate (EGCG) dimer, have been reported to attenuate CRC cell invasion, their capacity to directly modulate MMP-2 activity remains unclear. This work investigated the molecular mechanisms underlying the modulation of MMP-2 activity by ECG and EGCG dimers. Gelatin zymography revealed concentration-dependent reductions in recombinant MMP-2 gelatinolytic activity, with apparent IC50 values of 0.09 and 0.39 μM for ECG and EGCG dimers, respectively. Fluorescence quenching and isothermal titration calorimetry further demonstrated direct interactions between both dimers and MMP-2. Molecular modeling predicted that both dimers could bind near the catalytic region of MMP-2. In CRC cell models, ECG and EGCG dimers significantly decreased MMP-2 mRNA and protein levels while increasing tissue inhibitor of metalloproteinase-2 (TIMP-2) levels. These effects were accompanied by reduced gelatinase activity and suppression of CRC cell invasion. Collectively, these findings suggest that dimeric PCAs modulate MMP-2-associated gelatinolytic activity and regulate the MMP-2/TIMP-2 axis, providing mechanistic insights for their anti-invasive activity and supporting their potential as modulators of MMP-2-associated processes involved in CRC invasion.

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