ADP-ribosylation of the G protein Rho inhibits integrin regulation of tumor cell growth

Abstract

Using a gastric derived tumor line, we investigated the involvement of β1 integrin and Rho in cell growth regulation in response to collagen. The addition of C3 exoenzyme from Clostridium botulinum to specifically ribosylate and inhibit the function of the rho gene products inhibited cellular proliferation in a dose-dependent fashion. C3 exoenzyme exhibited broad cytostatic activity toward a number of tumor lines and induced G0/G1 accumulation, cyclin A inhibition, and pronounced alterations in cell morphology. Integrin-mediated adhesion to collagen led to the expression of the cyclin A gene whose expression could be blocked using anti-β1 integrin monoclonal antibodies. Phospholipid levels were induced upon β1 integrin- mediated adhesion to collagen, and the phospholipid induction was inhibited by either antibodies to β1 integrin or pretreatment of cells with C3 exoenzyme. Significant reduction in phospholipid levels correlated with proliferation for a panel of tumor lines deprived of adhesion to substrate. These results implicate a novel role for integrins and Rho in the regulation of tumor growth in response to matrix.