Interruption of homologous desensitization in cyclic guanosine 3',5'-monophosphate signaling restores colon cancer cytostasis by bacterial enterotoxins.
Bacterial diarrheagenic heat-stable enterotoxins induce colon cancer cell cytostasis by targeting guanylyl cyclase C (GCC) signaling. Anticancer actions of these toxins are mediated by cyclic guanosine 3',5'-monophosphate (cGMP)-dependent influx of Ca2+ through cyclic nucleotide-gated channels. However, prolonged stimulation of GCC produces resistance in tumor cells to heat-stable enterotoxin-induced cytostasis. Resistance reflects rapid (tachyphylaxis) and slow (bradyphylaxis) mechanisms of desensitization induced by cGMP. Tachyphylaxis is mediated by cGMP-dependent protein kinase, which limits the conductance of cyclic nucleotide-gated channels, reducing the influx of Ca2+ propagating the antiproliferative signal from the membrane to the nucleus. In contrast, bradyphylaxis is mediated by cGMP-dependent allosteric activation of phosphodiesterase 5, which shapes the amplitude and duration of heat-stable enterotoxin-dependent cyclic nucleotide accumulation required for cytostasis. Importantly, interruption of tachyphylaxis and bradyphylaxis restores cancer cell cytostasis induced by heat-stable enterotoxins. Thus, 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.
Pitari
Giovanni M
GM
Division of Clinical Pharmacology, Department of Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. gmpitari@yahoo.com
Baksh
Ronnie I
RI
Harris
David M
DM
Li
Peng
P
Kazerounian
Shiva
S
Waldman
Scott A
SA
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D001427:Bacterial Toxins / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004768:Enterotoxins / Q000494:pharmacology*; D029968:Escherichia coli Proteins; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000378:metabolism; D015398:Signal Transduction
D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D018000:Receptors, Peptide; C034151:heat stable toxin (E coli); C016276:8-bromocyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP; D002118:Calcium