Guanylyl cyclase C (GC-C) inhibits human colon carcinoma cell growth

Activation of GC-C in intestine by the E. coli heat-stable toxin (STa) or the endogenous ligands, guanylin and uroguanylin (UG), increases intracellular cyclic GMP (cGMP) regulating fluid and electrolyte homeostasis. The effect of STa and UG on cell growth and viability was examined in 3 human colon carcinoma cell lines. Treatment of T84 and Caco2 cultures, which express GC-C, with STa or UG (1 μM; 48 h) reduced (40-60%) the number of cells, protein content, metabolism of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), and [³H] thymidine incorporation. In contrast, incubation with STa or UG was without effect on SW480 cells, which do not express GC-C. STa or UG did not affect the viability of T84, Caco2 or SW480 cells. The cytostatic effect of STa was dose-dependent, reversible, mimicked by 8-bromo cGMP (5 mM) and not blocked by inhibitors of cyclic nucleotide-dependent protein kinases. Thus, STa and UG inhibit proliferation of human colon carcinoma cell lines by binding to GC-C and stimulating the accumulation of cGMP. These observations suggest that GC-C ligands may be novel cytostatic agents for the treatment of patients with metastatic colorectal cancer.