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Interruption of Homologous Desensitization in Cyclic Guanosine 3V,5V-Monophosphate Signaling Restores Colon Cancer Cytostasis by Bacterial Enterotoxins

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Interruption of Homologous Desensitization in Cyclic Guanosine 3V,5V-Monophosphate Signaling Restores Colon Cancer Cytostasis by Bacterial Enterotoxins Research Article Interruption of Homologous Desensitization in Cyclic Guanosine 3V,5V-Monophosphate Signaling Restores Colon Cancer Cytostasis by Bacterial Enterotoxins Giovanni M. Pitari, Ronnie I. Baksh, David M. Harris, Peng Li, Shiva Kazerounian, and Scott A. Waldman Division of Clinical Pharmacology, Departments of Pharmacology and Experimental Therapeutics and Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania Abstract Bacterial heat-stable enterotoxins induce secretory diarrhea in Bacterial diarrheagenic heat-stable enterotoxins induce colon endemic populations, travelers, and animal herds (8) by serving cancer cell cytostasis by targeting guanylyl cyclase C (GCC) as superagonists for the intestine-specific receptor guanylyl signaling. Anticancer actions of these toxins are mediated by cyclase C (GCC; ref. 9). Heat-stable enterotoxins, which have cyclic guanosine 3V,5V-monophosphate (cGMP)–dependent in- evolved to facilitate bacterial dissemination and propagation, flux of Ca2+ through cyclic nucleotide-gated channels. However, exemplify molecular mimicry of the endogenous hormones prolonged stimulation of GCC produces resistance in tumor guanylin and uroguanylin, which mediate autocrine/paracrine cells to heat-stable enterotoxin–induced cytostasis. Resistance control of intestinal fluid and electrolyte homeostasis by acti- V V reflects rapid (tachyphylaxis) and slow (bradyphylaxis) mech- vating GCC and inducing cyclic guanosine 3 ,5 -monophosphate anisms of desensitization induced by cGMP. Tachyphylaxis is (cGMP)–dependent chloride efflux through the cystic fibrosis regulator channel (10–12). Intriguingly, longitudinal exposure to mediated by cGMP-dependent protein kinase, which limits the conductance of cyclic nucleotide-gated channels, reducing the heat-stable enterotoxin–producing bacteria seems to protect influx of Ca2+ propagating the antiproliferative signal from endemic populations against colon cancer by reducing rates of the membrane to the nucleus. In contrast, bradyphylaxis is enterocyte proliferation (13) and intestinal tumorigenesis (14). In mediated by cGMP-dependent allosteric activation of phos- contrast to fluid and electrolyte secretion, regulation of phodiesterase 5, which shapes the amplitude and duration of intestinal cell proliferation by heat-stable enterotoxin–induced heat-stable enterotoxin–dependent cyclic nucleotide accumu- activation of GCC consists of cGMP-dependent stimulation of Ca2+ entry through cyclic nucleotide-gated (CNG) channels (13). lation required for cytostasis. Importantly, interruption of 2+ tachyphylaxis and bradyphylaxis restores cancer cell cytostasis Heat-stable enterotoxin–induced Ca currents, in turn, are induced by heat-stable enterotoxins. Thus, regimens that coupled to suppression of DNA synthesis (13) and tumor cell incorporate cytostatic bacterial enterotoxins and inhibitors cytostasis (15). of cGMP-mediated desensitization offer a previously unrecog- Normally, GCC is selectively expressed in apical membranes of nized therapeutic paradigm for treatment and prevention of enterocytes, ‘‘outside’’ mucosal cell tight junctions, and inaccessible colorectal cancer. (Cancer Res 2005; 65(23): 11129-35) to the systemic vascular compartment (10, 16, 17). Intestinal epithelial cells that have undergone neoplastic transformation overexpress functionally competent GCC (18) displayed on their Introduction surface during metastatic dissemination to extraintestinal tissues, Colorectal cancer is the third most common, and the second making it paradoxically accessible to the systemic vascular most deadly, cancer in the developed world (1, 2). The mortality compartment (19, 20). Indeed, GCC represents a unique target rate for colon cancer, 50%, reflects metastatic disease progression for selectively delivering imaging and therapeutic agents to (1) and the lack of efficacious adjuvant chemotherapy (3). Indeed, metastatic colorectal tumors in vivo (16, 17). Moreover, GCC f20% of patients have unresectable disease at presentation and agonists have been proposed as novel cytostatic agents for targeted f the majority of patients (>90%) that develop metastases ( 33%) do therapy for colorectal cancer metastases (13). However, receptor not benefit from current pharmacotherapeutic interventions (1, 3). desensitization (21–23) and activation of phosphodiesterases Major obstacles to the development of effective therapeutic (21, 24) represent mechanisms by which colorectal cancer cells regimens include the genetic and phenotypic heterogeneity of could develop resistance to cGMP-dependent cytostasis, limiting colorectal tumors (4) and the emergence of drug-induced adaptive the therapeutic potential of GCC ligands. escape mechanisms in cancer cells (5). Thus, individualized The present study reveals the previously unrecognized emer- therapy, more effective molecular targets, and strategies to gence of homologous desensitization of GCC-mediated cell cycle circumvent drug resistance are paramount for future therapeutic regulation in human colon cancer cells. Thus, elevations in paradigms for colon cancer (6, 7). intracellular cGMP ([cGMPi]) induce rapid (tachyphylaxis) and slow (bradyphylaxis) mechanisms of desensitization, imposed by the integrated regulation of discreet cGMP-dependent effectors, Note: S.A. Waldman is the Samuel M.V. Hamilton Professor of Medicine of Thomas which prevent GCC-mediated cytostasis. Importantly, interruption Jefferson University. Requests for reprints: Giovanni Mario Pitari, Division of Clinical Pharmacology, of the molecular mechanisms underlying tachyphylaxis and Thomas Jefferson University, 1100 Walnut Street MOB 811, Philadelphia, PA 19107. bradyphylaxis permits sustained inhibition of cancer cell prolifer- Phone: 215-955-5647; Fax: 215-955-7006; E-mail: [email protected]. I2005 American Association for Cancer Research. ation by GCC ligands without the development of escape or doi:10.1158/0008-5472.CAN-05-2381 resistance. www.aacrjournals.org 11129 Cancer Res 2005; 65: (23). December 1, 2005 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. Cancer Research Materials and Methods mmol/L sodium acetate (pH 4.0) followed by boiling for 3 minutes. cGMP production was linear with respect to time and protein concentration. Reagents. Eagle’s MEM (EMEM), Ca2+-free minimal essential medium Reverse transcription-PCR. Total RNA (1 Ag) from human retina (S-MEM), L-glutamine, and other reagents for cell culture were obtained (positive control, purchased from BD Biosciences, Franklin Lakes, NJ) and from Life Technologies, Inc. (Rockville, MD). Fetal bovine serum (FBS) and T84 cells (obtained with the Qiagen RNA Easy kit, Qiagen, Valencia, CA) the DMEM/F12 were from Mediatech, Inc. (Herndon, VA). Native heat-stable underwent reverse transcription with Superscript II (Life Technologies, enterotoxin was prepared as described (15). 45Ca2+ (24 mCi/mL) 3 Gaithersburg, MD), and resultant oligo(deoxythymidine)18-primed cDNAs was purchased from ICN Biochemicals, Inc. (Costa Mesa, CA). [methyl- H] were subjected to PCR for 35 cycles (94jC for 30 seconds, 60jC for 30 Thymidine (1 mCi/mL) was obtained from Amersham Pharmacia Biotech, seconds, and 72jC for 30 seconds) using Taq DNA polymerase (Applied Inc. (Piscataway, NJ). RP8pCPT-cGMPS was from Biolog Biochemicals (San Biosystems, Inc., Foster City, CA). CNGA1 channel mRNA was detected with Diego, CA), whereas Zaprinast, 8-br-cGMP, milrinone, propidium iodide, and sense (5V-TCTGAGGATGATGACAGTGCC-3V) and antisense (5V-CAGG- all other chemicals were from Sigma Chemical Co. (St. Louis, MO). TACTGCTCCCTCTGTGAT-3V) primers designed to amplify a product of Cell culture. T84 (passages 40-60) human colon carcinoma cells f123 bp. PCR products were subjected to electrophoresis on 2% agarose (American Type Culture Collection, Manassas, VA) were maintained at gels in Tris-borate EDTA buffer [90 mmol/L Tris borate, 2 mmol/L EDTA j 37 C (5% CO2) in DMEM/F12 containing 2.5 mmol/L L-glutamine, 100 (pH 8.3)] containing ethidium bromide and visualized by transillumination. A IU/mL penicillin, 100 g/mL streptomycin, and 10% FBS. Cells were fed Template-negative controls were run in each PCR experiment. every third day and split when subconfluent. Calcium transport. Exponentially growing T84 cells (f60% confluent in Cell proliferation. Proliferation of cancer cells was quantified in 96-well 24-well plates) were incubated in S-MEM containing low (300 Amol/L) 3 plates by [methyl- H]thymidine (0.2 ACi/well) incorporation into DNA (15). CaCl (13). Cells were pretreated with heat-stable enterotoxins for the 3 2 Cells were pulse-labeled (3 hours) with [ H]thymidine at the end of indicated times followed by washing (37jC, thrice) with incubation respective stimulation periods. For studies examining cancer cell cytostasis, medium. Then, unidirectional 45Ca2+ fluxes induced by heat-stable enter- f 50,000 cells per well were plated, permitted to recover for 6 hours, and otoxins (1 Amol/L, 20 minutes) were quantified (13). synchronized for 18 hours with FBS-free DMEM. Then, cells were stimulated Statistics. Reversetranscription-PCRexperimentsweredonein to proliferate (up to 34 hours) by adding 10% FBS, in the presence of the duplicate and repeated twice. Studies of calcium transport were done in indicated treatments. For studies examining acute regulation of DNA duplicate and expressed as mean F SE of four separate experiments. All f synthesis, exponentially growing cancer cells (
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