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Corticosteroids and Phosphatidylcholine Biosynthesis in Microsomal Fractions from L5178Y Lymphoma1

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Corticosteroids and Phosphatidylcholine Biosynthesis in Microsomal Fractions from L5178Y Lymphoma1 [CANCER RESEARCH 36, 1545-1550, May 1976] Corticosteroids and Phosphatidylcholine Biosynthesis in Microsomal Fractions from L5178Y Lymphoma1 George Melnykovych,2 Mary M. Standaert, Edna R. Matthews, and Susan L. Gray Research Service, United States veterans Administration Hospital, Kansas City, Missouri 64128 (0. M., M. M. S., S. L. G.j, and Department of Microbiology, University of Kansas Medical School, Kansas City, Kansas 66103 1G. M., E. R. M.J SUMMARY pe?iod was required for the growth inhibition to become manifest or that a limiting nutrient in the medium had to be Microsomal fractions from mouse lymphoma L5178Y and exhausted before the cells became susceptible to the toxic from rat thymocytes were used to follow incorporation of effects of the hormone. A search among several alternate rad iolabel from cytid me d iphosphate-[methyl-'4C]cho line possibilities led to the observation that incorporation of into microsornal lipids. Dexamethasone, at concentrations choline into PL' was inhibited by glucocorticoids in either ranging from 2.8 x 10@M to 2.8 x 10@M, partially inhibited synchronized or logarithmically growing cells, provided the this transfer reaction. Microsomes prepared from freshly latter were first depleted of choline (22). Neither choline isolated thymocytes were more sensitive to the effects of uptake nor its phosphorylation appeared to be involved in dexamethasone showing inhibition at concentrations of the steroid effect. Further studies of this system (16) have steroid as low as 2.8 x 10@ M. The inhibitory effect did not shown that microsomal fractions from L5178Y cells could depend on the amount of the available endogenous diglyc incorporate choline by 2 alternate pathways including the enides and was not related to a possible stimulation of “direct―Ca2@-stimulatedexchange of choline and the so cytidine diphosphate choline transferase back reaction by called Kennedy pathway. The latter involves phosphoryla the steroid. tion of choline to phosphorylcholine followed by the forma The survey of a broad selection of different steroids re tion of CDP-choline with the subsequent transfer of choline vealed a lack of correlation between the known lymphocyto to a diglyceride acceptor yielding PL and CMP (10). Prelimi lytic properties of steroids and their effects on cytidine nary results utilizing microsomal fraction from cells ex diphosphate choline transferase. Dexamethasone was the posed to steroids during growth indicated that CDP-choline only steroid of the glucocorticoid group that inhibited this transferase (CDP-choline:1 ,2-diglycenide choline phospho reaction in microsomal fractions of L5178Y lymphoma. The transferase, EC 2.7.8.2) was inhibited while the choline ex structural requirement for the inhibitory effect was related change reaction was unaffected (20). This work has now to the absence of oxygen functions in positions 11 and 17 of been extended to include experiments in which steroids the steroid and, possibly, to the presence of both C-20 and have been added directly to the reaction mixture without C-21 on the side chain. previous treatment of intact cells. INTRODUCTION MATERIALS AND METHODS For the most part, recent studies on the mode of action of Cells and Media. The origin and the procedure for grow steroids toward lymphatic cells have been concerned with ing L5178Y cells have been described in detail in an earlier identification of steroid receptors (1, 2, 12). Attempts to ex paper (21). For these experiments the cells were grown in plain the emergence of steroid-resistant clones among pop suspension in Fischer's medium (Grand Island Biological ulations of susceptible cells have led to the proposal that Co., Grand Island, N. Y.) supplemented with 10% horse the resistance to the cytolytic effects is related to the ab serum; penicillin G, 100 units/mI; and streptomycin sulfate, sence of specific steroid-binding molecules (18). Neverthe 200 j.@g/ml.The cells were monitored regularly for Myco less, this important finding does not change the fact that, in plasma and were found to be free of contamination. biochemical terms, there is very little information about the Growth Experiments. For growth measurement, the mechanism of steroid-induced lymphocytolysis. Some time L5178Y cells were inoculated at the density of 5 x 10@cells/ ago we reported (21) that, in synchronous cultures of ml into 50-mI Erlenmeyer flasks containing 10 ml of growth L5178Y lymphoma, the growth-inhibitory effect could not be medium and were grown on a rotary shaker at 75 rpm at 37° seen unless the cells have been exposed to the hormone for in 5% CO2 in air. The incubation times varied from 12 to 90 at least 1 growth cycle. This suggested that either a long lag hr. In some experiments delipidized serum proteins from whole sera according to the procedure of G. Rothblat (per I This investigation was supported in part by USPHS Research Grant CA 08315 from the National Cancer Institute. sonal communication) were used. At the end of each incu 2 To whom requests for reprints should be sent, at: Research Service (151), Veterans Administration Hospital, 4801 Linwood Boulevard, Kansas City, Mo. 3 The abbreviations used are: PL phosphatidylcholine; CDP-choline, cyti 64128. dine diphosphate choline; HEPES, N-2-hydroxyethylpiperazine-N'-2-ethane Received October 28, 1975; accepted January 16, 1976. sulfonic acid; DEX, dexamethasone. MAY 1976 1545 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1976 American Association for Cancer Research. G. Melnykovych et a!. bation period cells were enumerated in a Model B Coulter activity. At the end of the incubation period, 1-ml portions of counter. the incubation mixture were added to 8 ml of metha Thymocytes. Adrenalectomized male rats weighing ap nol:chloroform (1:1). The mixture was kept in the cold room proximately 150 g were obtained from Charles River Farms, overnight and then extracted according to a modified pro North Wilmington, Mass., and were sacrificed 10 days post cedure of Folch et a!. (8) as previously described (16). adrenalectomy. The thymocyte suspensions were prepared Briefly, the method involved filtration of the extract through according to the method of Munck (17). glass wool, reextraction with chloroform, and washing the Preparation of Microsomal Fractions. Freshly harvested extract 6 times to remove CDPcholine. After the final wash, L5178Y cells or freshly isolated thymocytes were washed in the lower phase was evaporated to dryness in scintillation 0.85% NaCl solution and were suspended in 1 mM phos vials and dissolved in a toluene-based scintillation fluid (5 g phate buffer, pH 7.4, that contained 1 mM MgCI2 and 0.32 M PPO and 0.12 g POPOP per liter of toluene). The samples sucrose (14). They were disrupted in the cold by homogeni were counted in a Packard Tni-Carb scintillation spectrome zation and then subjected to a differential centnifugation ten, and the results were expressed as dpm/mg of microso procedure as previously described (16). The clean microso mal protein as determined by the procedure of Lowry et a!. mal pellet isolated from the final centnifugation at 111,000 x (13). g was resuspended in 0.27 M sucrose. The preparations For the study of the back reaction of CDP-choline trans were stored at —20°andwere found to retain their activity ferase, the microsomal fractions from L51 78Y cells that had for at least 1 month. been grown in the presence of [methy!-'4C]choline were CDP-Choline Transferase. The reaction mixture con incubated at 37°for30 mm in the reaction mixture contain tamed o.s to 0.8 mg microsomal protein, 20 mM HEPES ing 20 mM HEPES buffer (pH 7.5), 34 mM sucrose, 1 mM buffer (pH 7.5), 34 mM sucrose, 1 mM MgCI2 and 0.12 @Ci MgCI2, and 4 x 1O@MCMP. The radioactivity in the microso CDP-[methyl-'4C]choline chloride in a final volume of 2.4 ml. mal lipid fraction was determined as described above. The preparations were incubated at 37°forvarious times. As Steroids. The complete list of steroids used is shown in shown previously (16), the reaction proceeded linearly with Table 1. They were dissolved in absolute ethanol. Appropni time for at least 30 mm. This was the usual time used to ate ethanol controls were included with all experiments. determineeffectofsteroidson CDP-cholinetransferase Radioactive Isotopes. The CDP-[methy!-‘4C]choline(spe Table 1 Effects of selectedsteroids on CDP-cholinetransferasein microsomalpreparations from L5178Ycells Cellswere grown in Fischer'smediumsupplementedwith 10%horseserum.The microsomalfractions from cells grown for 72 hr at 37° were incubated in a mixture containing, in a final volume of 2.4 ml, 20 mM HEPES buffer pH 7.5, 34 mM sucrose, 1 mM MgCI2,0.12 j@CiCOP [methyl-'4C]cholinechloride, and the indicated concentrations of steroids. The radioactivity in the lipid fraction was determined after incubation at 37°for 30 mm. COP-cholinetransferaseRelative activity of (% of control) at fol concentrationsTrivial lowing steroid M2.8. 1O@ nameSteroid chemical namex 0.10Deoxycorticosterone21-Hydroxy-4-pregnene-3,20-dione22 1.0 0.28 76Progesterone4-Pregnene-3,20-dione48 35 58 785a-Pregnanedione5a-Pregnan-3,20-dione77 64 88 106Pregnenolone3j3-Hydroxy-5-pregnen-20-one26 55 72 56Dexamethasone9a-Fluoro-1 12 40 88Corticosterone1 1/3,17,21 -trihydroxy-1 6co-methyl-1 ,4-pregnadiene-3,20- 56 84 dione47 95Cortexolone17a,21-Oihydroxy-4-pregnene-3,20-dione981f3,21-Dihydroxy-4-pregnene-3,20-dione96 1175f3-Pregnanedione5/3-Pregnan-3,20-dione72 1101 100 104 7a-Pregnenolone3f3,l7cs-Oihydroxy-5-pregnen-20-one93f3-Methasone9a-Fluoro-1
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