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Adenosine Formation and Metabolism During Adenosine Triphosphate Catabolism in Ehrlich Ascites Tumor Cells1

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Adenosine Formation and Metabolism During Adenosine Triphosphate Catabolism in Ehrlich Ascites Tumor Cells1 [CANCER RESEARCH 33, 2825-2829, November 1973] Adenosine Formation and Metabolism during Adenosine Triphosphate Catabolism in Ehrlich Ascites Tumor Cells1 Christopher A. Lomax2 and J. Frank Henderson3 University of Alberta Cancer Research Unit (McEachern Laboratory) and Department of Biochemistry, Edmonton, Alberta, Canada T6G 2E1 SUMMARY phosphotransferase, EC 2.7.1.20) and adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) in the metabolism of Adenosine formation and metabolism were measured during the adenosine so produced. the course of 2-deoxyglucose-induced adenosine triphosphate (ATP) catabolism. Adenosine did not accumulate unless coformycin, an inhibitor of adenosine deaminase, was present. MATERIALS AND METHODS Following formation of adenylate from ATP, there are two Tumor Cells. Ehrlich ascites carcinoma cells were main routes by which adenylate can be converted to inosine: by tained by weekly i.p. transplantation of approximately 4 X dephosphorylation to adenosine followed by deamination and IO7 cells into ICR Swiss mice. After 5 or 6 days, the cells were by deamination to inosinate followed by dephosphorylation. removed and washed 3 times (or until free of erythrocytes) The major route of catabolism of adenylate formed from ATP with Fischer's medium (6) modified by the omission of was deamination, but up to 18% of the adenylate was bicarbonate and the addition of sodium phosphate to a final catabolized by dephosphorylation; the concentration of ATP phosphate concentration of 25 mM (4). This medium contains had no detectable influence on the relative rates of the 5.5 mM glucose. alternative pathways. Adenosine formed by dephosphorylation Measurement of ATP-14C Breakdown. A 2% cell suspension of adenylate may also be rephosphorylated and the rate of was incubated in modified Fischer's medium at 37°with rephosphorylation is governed by the intracellular concentra shaking at 120 oscillations per min. Incubation vessels were tion of ATP. 10-ml Erlenmeyer flasks containing 2 ml of the cell suspension. After 20 min of incubation, adenine-'4C was INTRODUCTION added (100 juM, final concentration) and incubation was continued for 30 min to synthesize radioactive ATP. After this Incubation of ascites tumor cells with 2-deoxyglucose anabolic phase, the cells were centrifuged, washed, and causes a rapid depletion of intracellular ATP, with a resuspended to 2% in fresh warmed medium containing either concomitant increase in the concentrations of ino'sine and 5.5 mM 2-deoxyglucose or a 5.5 mM hexose solution hypoxanthine (11). Following formation of adenylate from consisting of 2-deoxyglucose and glucose in the proportions ATP, there are 2 routes by which adenylate can be converted indicated in the text. Aliquots of 0.1 ml were removed at to inosine: (a) by dephosphorylation to adenosine, followed various intervals and added to tubes containing 0.005 ml of by deamination, and (b) by deamination to inosinate, followed ice-cold 4.2 M perchloric acid. Acid extracts were subse by dephosphorylation. Previous attempts (11, 13) to evaluate quently neutralized by the addition of 0.005 ml of 4.42 N the relative importance of these pathways have shown that K.OH. The total radioactivity in purine nucleotides, nucleo- adenosine concentrations remain very low during the course of sides, and bases was measured by means of the Chromato ATP catabolism to inosine. However, this result could be due graphie technique of Crabtree and Henderson (4). Results to a low rate of dephosphorylation of adenylate (Route a, presented are measurements of the amounts of radioactivity in above), to a high rate of rephosphorylation of adenosine, to a each metabolite, expressed in nmoles/g wet weight of cells, high rate of deamination of adenosine, or to various rather than the total amount of each metabolite. Data combinations of these, and it has not been possible to presented are the averages of duplicate samples in 1 distinguish among these possibilities. experiment and are representative of results obtained in at This paper reports attempts to measure the formation of least 2 experiments. Average deviation of individual analyses adenosine during 2-deoxyglucose-induced breakdown of ATP from the mean was less than 7%. and to estimate the roles of adenosine kinase (adenosine Chemicals. We are grateful to Professor H. Umezawa and Professor M. Hori, Institute of Microbial Chemistry, Tokyo, 'This work was supported by the National Cancer Institute of Japan, for providing us with coformycin, a specific and potent Canada. 'Present address: Biology Division, National Research Council of inhibitor of adenosine deaminase (9). The adenosine kinase inhibitor, 4-amino-5-iodo-7-|3-D- Canada, Ottawa, Ontario, Canada. 3To whom reprint requests should be addressed. ribofuranosyl-7//-pyrrolo[2,3-</] pyrimidine, was obtained Received February 28, 1973; accepted August 20? 1973. from the Cancer Chemotherapy National Service Centre, NOVEMBER 1973 2825 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1973 American Association for Cancer Research. Christopher A. Lomax and J. Frank Henderson National Cancer Institute, Bethesda, Md. Adenine-8-14C (50 xanthine and their ribonucleosides. The concentration of mCi/mmole) was purchased from New England Nuclear, radioactive adenosine fluctuates during the incubation period, Boston, Mass., and 2-deoxy-D-glucose and purine nucleotides, but large amounts do not accumulate. The major products that nucleosides, and bases were from Sigma Chemical Co., St. accumulate are radioactive inosine and hypqxanthine. Louis, Mo. Fischer's medium was purchased from Grand Island These results are similar to those of other workers, who Biological Co., Grand Island, N. Y. measured total amounts of ATP and its metabolites rather than those of just radioactive compounds. Control exper iments (A. S. Bagnara and J. F. Henderson, unpublished RESULTS results) have shown that the rates of catabolism of radioactive Adenosine Formation and Deamination. The results of an and nonradioactive ATP are similar under the conditions of experiment in which radioactive ATP breakdown was induced these experiments. Thus newly synthesized and other ATP do by 5.5 mM 2-deoxyglucose are shown in Chart 1 (open not appear to be compartmented in the cells. circles). The concentration of radioactive ATP falls very In attempts to evaluate the possibility that adenosine rapidly (over 80% in 4 min), and there are transient increases deaminase activity might be the basis of the low adenosine in the concentrations of radioactive ADP, adenylate, and concentrations measured in the experiment described above, a inosinate. Increases in the concentrations of radioactive specific inhibitor of this enzyme, coformycin (9), was used. In xanthylate and guanine nucleotides coincide with an increase the presence of coformycin (Chart 1, closed circles), the in the rate of accumulation of radioactive guanine and overall pattern of radioactive ATP breakdown is very similar to that seen in its absence. The concentration of radioactive adenylate increases to a greater extent and decreases more slowly in the presence of coformycin; however, at longer 3000 incubation times (not shown here), its concentration falls to its original level or lower. The other major effects of the addition of coformycin are the accumulation of large amounts of radioactive adenosine and reduced accumulation of radio active inosine and hypoxanthine. Thus adenosine is formed during the course of ATP breakdown, and rapid deamination is at least one important reason for its failure to accumulate. Control experiments have shown that coformycin has no effect on ATP metabolism in the absence of 2-deoxyglucose and has no effect on purine nucleotide synthesis and interconversion when cells are incubated with radioactive purine bases. If possible adenosine kinase activity is not considered for the moment (see below), an estimation of the relative rates of the 2 alternative pathways of adenylate catabolism can be calculated from these data. Thus, the radioactive adenosine which accumulates in the presence of coformycin may be taken to be a measure of adenylate dephosphorylation, whereas the sum of increases of radioactivity in inosinate, inosine, hypoxanthine, xanthylate, xanthosine, xanthine, uric acid, guanine nucleotides, guanosine, and guanine (Chart 2) may be taken to be a measure of adenylate deamination. These data are presented in Table 1. At early times, adenylate appears to be catabolized 10 20 predominantly by deamination. However, after 6 min, the proportion catabolized by dephosphorylation steadily in TIME (min) creases. Over the entire period of incubation, 17.2% of the Chart 1. Effect of 5.5 mM deoxyglucose on the intermediates of the adenylate formed from ATP is catabolized primarily by purine nucleotide catabolic pathway in the absence (o) and presence (•) dephosphorylation and, at longer times, this fraction rises to of the adenosine deaminase inhibitor coformycin. Radioactive ATP was 23% (unpublished data). synthesized by incubation of a 2% suspension of Ehrlich ascites carcinoma cells in modified Fischer's medium with adertine-'4C (100 Regulation of Adenylate Catabolism. Using extracts of rat hearts and lungs, Burger and Lowenstein (2) demonstrated MM).After 30 min, the cells were washed and resuspended in modified Fischer's medium containing 5.5 mM 2-deoxyglucose and no glucose. that ATP could influence the route of adenylate catabolism by Samples were taken at time intervals, and the acid-soluble
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