PI-25Interruption of homologous desensitization in cGMP signaling restores colon cancer cytostasis by bacterial enterotoxins

Abstract

BACKGROUND Bacterial diarrheagenic heat-stable enterotoxins (STs) induce colon cancer cell cytostasis by targeting guanylyl cyclase C (GCC) signaling. Although the molecular pathway involving cGMP-dependent influx of Ca2+ through cyclic nucleotide-gated (CNG) channels has been elucidated, the long-term kinetics of the antineoplastic effects of these toxins remain undefined. METHODS GCC signaling inducing cytostasis was examined in human colon carcinoma T84 cells employing radioimmunoassay for cGMP, unidirectional 45Ca2+ current, 3H-thymidine incorporation into the DNA and flow cytometry. RESULTS Prolonged stimulation of GCC produced resistance in tumor cells to ST-induced cytostasis. Resistance reflected rapid (tachyphylaxis) and slow (bradyphylaxis) mechanisms of desensitization induced by cGMP. Tachyphylaxis was mediated by cGMP-dependent protein kinase, which reduced the influx of Ca2+ through CNG channels. In contrast, bradyphylaxis was mediated by cGMP-dependent allosteric activation of phosphodiesterase 5, which shapes the amplitude of ST-dependent cyclic nucleotide accumulation required for cytostasis. Importantly, interruption of tachy- and bradyphylaxis restored cancer cell cytostasis induced by ST. CONCLUSIONS Regimens that incorporate cytostatic bacterial enterotoxins and inhibitors of cGMP-mediated desensitization offer a previously unrecognized therapeutic paradigm for treatment and prevention of colorectal cancer. Clinical Pharmacology & Therapeutics (2005) 79, P13–P13; doi: 10.1016/j.clpt.2005.12.046