Abstract
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.
Highlights
Colorectal cancer is the third most common, and the second most deadly, cancer in the developed world [1, 2]
The present study reveals the previously unrecognized emergence of homologous desensitization of guanylyl cyclase C (GCC)-mediated cell cycle regulation in human colon cancer cells
Desensitization of the antiproliferative effects of heat-stable enterotoxins was associated with a reduced ability of that enterotoxin to elevate [cGMP]i (Fig. 1D), which mediates cytostasis produced by GCC [13, 15]
Summary
Colorectal cancer is the third most common, and the second most deadly, cancer in the developed world [1, 2]. The mortality rate for colon cancer, 50%, reflects metastatic disease progression [1] and the lack of efficacious adjuvant chemotherapy [3]. F20% of patients have unresectable disease at presentation and the majority of patients (>90%) that develop metastases (f33%) do not benefit from current pharmacotherapeutic interventions [1, 3]. Major obstacles to the development of effective therapeutic regimens include the genetic and phenotypic heterogeneity of colorectal tumors [4] and the emergence of drug-induced adaptive escape mechanisms in cancer cells [5]. Individualized therapy, more effective molecular targets, and strategies to circumvent drug resistance are paramount for future therapeutic paradigms for colon cancer [6, 7].
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