Gastrins, including amidated
gastrin (Gamide) and
glycine-extended
gastrin (Ggly), are known to accelerate the growth of gastric and
colorectal cancer cells by stimulation of proliferation and inhibition of apoptosis. Gamide controls apoptosis by regulation of
proteins of the Bcl-2 family and by regulation of the activation of
caspases. However the interactions between Ggly and
proteins of the Bcl-2 family and
caspases are not known. Since in other systems
G proteins of the Rho family inhibit apoptosis via interaction with
proteins of the Bcl-2 family, leading to changes in
caspase activities, we have compared the role of Rho family
G proteins in regulation of Bcl-2-like (Bad/Bax/
Bcl-xl) protein expression and
caspase 3 activation by Ggly and Gamide. The effects of the specific inhibitors C3 (for Rho) and
Y-27632 (for ROCK), and of dominant negative mutants of Rac, Cdc42 and PAK, were investigated in the gastric epithelial cell line IMGE-5. Apoptosis was induced by serum
starvation and confirmed by
annexin V staining and
caspase 3 activation. Ggly inhibits
caspase 3 activation via a Bcl-2-like
protein-mediated pathway which requires activation of both Rho/ROCK and Rac/Cdc42/PAK. Gamide inhibits
caspase 3 activation via redundant Bcl-2-like
protein-mediated pathways which involve alternative activation of Rac/Cdc42/PAK and Rho/ROCK. Gamide and Ggly differentially activate members of Rho family
G proteins which in turn regulate different
proteins of the Bcl-2 family leading to changes in
caspase 3 activity. The findings offer potential targets for blocking the growth-stimulating effects of these
gastrins.