Regulation of cell surface molecules by
matrix metalloproteinases (
MMPs), as well as
MMPs-catalyzed degradation of extracellular matrix, is important for
tumor invasion and
metastasis. Our previous study (Kioi, M., Yamamoto, K., Higashi, S., Koshikawa, N., Fujita, K., and Miyazaki, K. (2003) Oncogene 22, 8662-8670) demonstrated that active
matrilysin specifically binds to the surface of
colon cancer cells and induces notable cell aggregation due to processing of the
cell membrane protein(s). Furthermore, these aggregated cells showed a dramatically enhanced metastatic potential. To elucidate the mechanism of
matrilysin-induced cell aggregation, we attempted to identify the
matrilysin-binding substance on the cell surface. Here, we demonstrate that
cholesterol sulfate on the cell surface is a major
matrilysin-binding substance. We found that active
matrilysin bound to the cell membrane and
cholesterol sulfate incorporated into
liposomes with similar affinities. Treatment of
colon cancer cells with
beta-cyclodextrin significantly reduced not only
matrilysin binding to the cell surface but also
matrilysin-dependent proteolysis and cell aggregation. Interestingly, replenishment of
cholesterol sulfate, but not
cholesterol, neutralized the effects of
beta-cyclodextrin. Taken together, it is likely that binding of
matrilysin to
cholesterol sulfate facilitates the
matrilysin-catalyzed modulation of
cell surface proteins, thus inducing the
cancer cell aggregation.