Anti-oral cancer strategy by means of inhibition of cellular adhesion to extracellula matrices

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We have analyzed anti-cancer effect in a situation in which adhesion of oral carcinoma cells to extracellular matrices is inhibited. To this end, suramin, a polysulfonated naphthylurea, which has been used as an anti-trypanosoma reagent but has also known as an inhibitor of lysosomal heparanase, was used for inhibition of adhesion of oral carcinoma cells, such as ACC3 cells of human salivary adenoid cystic carcinoma origin.ACC3 cells have been known to biosynthesize excessive amounts of extracellular matrix (ECM) molecules, especially basement membrane-associated molecules, such as heparan sulfate proteoglycan, HSPG/perlecan, and fibronectin. When ACCE cess were cultivated in the presence of 100 ;uM suramin, secretion of ECM molecules by ACC3 cells into the culture medium was enhanced. When 200 fM suramin was added, attachment of ACC3 cells to culture dishes reduced significantly. In the presence of suramin and RGD peptides, which are an ECM recoginition site of integrins, the attachme … More nt was two times more inhibited. Thus, it was suggested that suramin affected integrih-dependent cell adhesion. By day 7 of culture in the presence of suramin, ECM molecules were shed more prominently into the culture medium of ACC3 cells. Immunofluorescence showed that ECM molecules and integrins were localized within the cytoplasm but not in the extracellular space or in the cell surface. These results indicated suramin inhibited cell membrane assembly of integrin and consequently trapping of ECM molecules by cell surface integrins.Immunoprecipitation and pulse-chase experi-ments showed that suramin inhibited biosynthesis of an unknown molecule with Mr. 120 kDa, which was co-precipitated with integrin a5. Immunoblotting experiments showed that the 120 kDa molecule was focal adhesion kinase (FAK), which functions in phospholylation of integrins. The results indicated that suramin inhibit FAK expression of ACC3 cells, which resulted in integrin function in cellular attachment.These results clearly indicate that the inhibition of cell surface receptors for ECM molecules can be one of the strategies for suppression of oral carcinoma cell growth. Less