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Eicosanoid Production by the Human Gastric Cancer Cell Line ACS and Its Relation to Cell Growth1

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Eicosanoid Production by the Human Gastric Cancer Cell Line ACS and Its Relation to Cell Growth1 [CANCER RESEARCH 52, 1744-1749. April 1. 1992] Eicosanoid Production by the Human Gastric Cancer Cell Line ACS and Its Relation to Cell Growth1 Shuya Shimakura and C. Richard Roland2 Gastroenlerology Section, VA Medical Center, and the Gastrointestinal Peptide Research Center, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105 ABSTRACT tumor cell lines. For example, certain members of the PGA, PGE, and PGD: series (including 12-PGJ2, the ultimate metab Eicosanoids have the ability to stimulate or inhibit the proliferation of epithelial cells, and they have been shown to modulate the growth olite of PGD2) are potent inhibitors of growth for certain characteristics of certain tumor cell lines. In addition, many epithelial cultured tumor cells (4-7). PGE?, which is abundantly produced cells have the ability to produce eicosanoids, which may then serve as by gastric tissue, has a significant suppressive effect on the autocrine growth factors. We have measured the eicosanoids produced growth of the human stomach cancer cell line Kato III (8). by the human stomach cell line AGS using reverse-phase high-perform Although not studied previously in gastrointestinal epithelium, ance liquid chromatography. AGS cells were incubated with |MIjarachi- it has been suggested that some lipoxygenase products may donic acid and stimulated to release eicosanoids by the calcium ionophore participate in the stimulation of the human leukemia cell line A23187. Unlike its counterpart from the normal stomach, the AGS tumor HL-60 (9). Work by several laboratories has suggested that cell line produced prominent amounts of the leukotrienes I).4,C4,and B4; 6-keto-prostaglandin !•',.:thromboxane B2; hydroxyeicosatetraenoic tumors of the gastrointestinal tract may synthesize eicosanoid acids; and smaller amounts of other prostaglandins in response to products that differ from those found in the corresponding A23187. Under basal condition (in the absence of calcium ionophore), normal tissue (10, 11). However, these studies have not defini hydroxyeicosatetraenoic acid was produced in greatest relative amount tively ascertained the profile of eicosanoids derived from tumor compared with the other eicosanoids. tissue itself, because of the presence of inflammatory cells in To elucidate the potential autacoid role of these agents, exogenous fresh tumor tissue (12, 13). A cultured cell line permits a eicosanoids were added to AGS cells, and proliferation was measured. Prostaglandins I>;and E2 suppressed the growth of AGS cells in a dose- determination of eicosanoid production by the epithelial cells unambiguously; however, it is possible that cultured tumor cells dependent manner. On the other hand, leukotrienes D4 and (., had a dose-dependent proliferative effect on cell growth. The lipoxygenase do not perfectly reflect the behavior of tumors in vivo. inhibitor nordihydroguaiaretic acid (10 ", II) s M) and hydrocortisone We have hypothesized that some tumor cells may gain a (11) * M) had dose-dependent suppressive effects on growth, whereas growth advantage by losing their ability to synthesize growth- indomethacin (IO"6 M and 10~*M) had no effect. These results suggest suppressive PGs and by producing greater amounts of growth- that AGS cells preferentially metabolize arachidonic acid through the 5- stimulatory eicosanoids. To test this hypothesis, we measured lipoxygenase pathway, which results in the production of growth-stimu the eicosanoid-metabolizing capacities of the human gastric latory autocoids. Agents that selectively block this arm of eicosanoid cancer cell line AGS using [3H]AA as a metabolic precursor metabolism might be useful therapeutic agents in the treatment of certain and identified the eicosanoid metabolites using reverse-phase gastrointestinal cancers. HPLC. We found that AGS cells produced a different profile of eicosanoid metabolites than what has been reported previ INTRODUCTION ously from normal gastric mucosal cells, that members of the PG family suppressed the growth of AGS cells, and that LTs Eicosanoids are important autocoids that are known to reg ulate a wide range of physiological processes in gastrointestinal had a proliferative effect on these cells. epithelia including the secretion of fluid and electrolytes, mu- cosal blood flow, and cell proliferation (1,2). Cells vary in their ability to metabolize AA,3 and it is becoming apparent that MATERIALS AND METHODS each cell type may have a unique ability to produce PCs, LTs, Materials and other related eicosanoids. It has long been known, for example, that normal gastric epithelium produces certain PGs, The following reagents were purchased from Sigma Chemical Co. but has a relatively limited ability to produce LTs, which may (St. Louis, MO): calcium ionophore A23187; DMSO; PGE2, PGD2, be prominently produced by certain inflammatory cells (3). BSA, HBSS, PCA; trifluoroacetic acid; 6-keto-PGF,„,PGE2, PGD2, Many eicosanoids have been shown to affect the growth of PGF2o, TxB2; trypan blue; indomethacin; NDGA; BrdU; and hydrox- yurea. LTB4, LTC4, LTD4, 12-HHT and 12- and 15-HETE were Received 7/3/91; accepted 1/17/92. purchased from Cayman Chemical (Ann Arbor, MI). IMDM and The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in trypsin (0.25%) EDTA (1 mM) were purchased from GIBCO Labora accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tories (Grand Island, NY). Heated-inactivated FBS was from Hyclone, ' Supported in part by NIH Grants R01DK37489 and P30-DK 34933 and by Logan, UT. ['H]AA (243 mCi/mmol) and ['Hjthymidine were pur the Research Service of the Department of Veterans Affairs. 2To whom requests for reprints should be addressed, at GI Section (HID), chased from New England Nuclear (Wilmington, DE). HPLC-grade VA Medical Center, 2215 Fuller Road, Ann Arbor, MI 48105. acetonitrile and methanol were purchased from Mallinckrodt, Inc. 3The abbreviations used are: AA, arachidonic acid; PG, prostaglandin; LT, (Paris, KY). The tissue culture plates were purchased from Costar leukotriene; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide; BSA, bovine serum albumin; HBSS, Hanks' balanced salt solution; (Cambridge, MA). Anti-BrdU monoclonal antibody was purchased PCA, perchloric acid; I \B;. thromboxane B:: NGDA, nordihydroguaiaretic acid; from Vector Laboratory (Burlingame, CA). Protein was measured using BrdU, 5-bromo-2'-deoxyuridine; 12-HHT, 12-hydroxyheptadecatrienoic acid; the Coomassie blue reagent of Pierce (Rockford, IL). All reagents were HETE, hydroxyeicosatetraenoic acid; IMDM, Iscove's modified Dulbecco's me dium; FBS, fetal bovine serum; PBS, phosphate-buffered saline; LI, labeling of highest grade available, and all water was deionized and passed index; PLA3, phospholipase A2; HPETE, 15-L-(i)-hydroperoxyeicosatrienoic through a MilliQ purification system (Waters Associates, Milford, MA) acid. prior to use. 1744 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1992 American Association for Cancer Research. EICOSANOIDS SYNTHESIS BY ACS CELLS Methods significantly different in each series of experiments. |3H]Thymidine Incorporation. ACS cells (2 x 10~5) prepared as de scribed above were incubated for 24 h, to which [3H]thymidine was Eicosanoids Synthesis by ACS Cells added at a specific activity of 0.5 mCi/ml. To estimate nonspecific Cell Culture and Loading with [3H|AA. Two ml of an ACS cell incorporation or adherence of thymidine, 10 ml of hydroxyurea (10 suspension (2 x IO6cells/ml) were plated in tissue culture wells, loaded mg/ml) were added to some wells. Two h later, 2 ml of ice-cold saline with 0.5 mCi of [3H]AA per well, and incubated at 37°Cunder 5% CO2 were added, aliquots were removed, and cells were washed twice with and 95% air. After 18 h of incubation, the labeling medium and floating PBS. After counting cell numbers, 2 ml of 5% PCA were added, and cells were removed, and the cells were washed twice with HBSS con the dpm value in the acid-insoluble fraction was measured. BrdU LI. To measure DNA synthesis, 2 x IO6 ACS ceils were taining 2% BSA and once with HBSS containing 0.1% BSA to remove free unincorporated [3H]AA. prepared as described above, after which Bull was added at a final Extraction of 3H-labeled Eicosanoids. The ACS cell (14) monolayers concentration of 100 mg/ml for 4 h. To terminate BrdU labeling, ice- were incubated in 2 ml of IMDM supplemented with 10% FBS in the cold PBS was added to the wells, and the supernatant was discarded. presence or absence (using vehicle as control) of 2.0 or 5.0 mM A23187 BrdU-labeled cells were washed twice with PBS and removed from the in DMSO (at a final DMSO concentration of 0.02%) for 1 h. The wells with trypsin/EDTA. Cells were attached to glass slides by cen- extraction from culture medium of radiolabeled eicosanoids produced trifugation using a Cytospin-2 centrifuge (Shandon, Pittsburgh, PA) by the [3H]AA-labeled ACS cells was performed by the method of and fixed in 70% ethanol. Cells on the glass slides were treated with 4 Wescott et al. (15). After l h of incubation, culture media from three N HC1 for 30 min to denature the DNA, and immunohistochemical wells were pooled and added to two volumes of ice-cold methanol. The detection of BrdU incorporation was performed using the anti-BrdU mixture was centrifuged at 1500 rpm for 5 min, and the methanolic monoclonal antibody and the avidin-biotin-peroxidase complex method supernatant was diluted in 0.1 M sodium phosphate buffer, pH 7.4, to (16). To calculate the BrdU LI, photographs were taken of at least four yield a final methanol concentration of 20%. This 80% aqueous mixture different highpower fields randomly selected under the light micro was applied to Sep-Pac CIS cartridges (Waters Associates, Milford, scope. Total cells and BrdU-positive nuclei were counted in each field. MA) that had been prewashed sequentially with 20 ml of methanol and The LI was defined as the ratio of BrdU-labeled cells to total cells 20 ml of deionized water.
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