Modulation of the Growth of a Human Erythroleukemic Cell Line (K562) by Prostaglandins: Antiproliferative Action of Prostaglandin A1

[CANCER RESEARCH 46, 6073-6077, December 1986] Modulation of the Growth of a Human Erythroleukemic Cell Line (K562) by Prostaglandins: Antiproliferative Action of Prostaglandin A1

M. Gabriella Santoro,2 Antonella Crisari, Arrigo Benedetto, and Carla Amici

Institute of Experimental Medicine, C. N. R., II University of Rome, Via O. Raimando, 00173 Rome [M. G.S., A. C.J, and Center of Virology, Osp. S. Camilla, C. Gianicolense 85, 00152 Rome [A. B., C. A.J, Italy

ABSTRACT proliferation and metabolic activity of a human erythroleukemic cell line, the K562 cells. Among several prostaglandins (PCs) tested, PGFiâ€žwas found to slightly enhance, while PGAs and PGDs were found to drastically inhibit the growth of K562 cells in culture. This effect was dose dependent. While PGD2 was cytotoxic, PGA, treatment could totally inhibit K562 MATERIALS AND METHODS cell proliferation, without affecting cell viability. PGA, action was re versible; however, K562 cells totally lost their growth potential after Chemicals. Prostaglandins and dbcAMP were obtained from Sigma prolonged exposure to PGAs. Chemical Co., St. Louis, MO. [methyPHlThymidine, [5,6-3H]uridine, While it did not significantly affect DNA and RNA synthesis, PGA, [35S]methionine, D-[6-3H]galactose, and MC-methylated protein mixture partially inhibited protein synthesis and glycosylation in these cells. In were obtained from Amersham Int., Buckinghamshire, England. 16,16- particular, the production of two polypeptides with molecular weights of Dimethyl-PGA2-methyl ester was kindly provided by Dr. J. Pike, the 92,000 and 46,000, respectively, was decreased, while the synthesis of a Upjohn Co., Kalamazoo, MI. RPMI 1640 medium and fetal bovine protein with a molecular weight of 74,000 was induced. serum were obtained from Flow Labs., Inc., McLean, VA. These results strongly support the concept that PGs are involved in Cell Culture. K562 cells were maintained in RPMI 1640 medium, the regulation of cell proliferation, and that PGs containing a reactive supplemented with 10% fetal bovine serum, glutamine, and antibiotics, a,(8-unsaturated carbonyl group in the cyclopentane ring are potential at 37Â°Cina 5% CÃœ2atmosphere. Cells were plated at a density of 2 x antineoplastic agents. 105/ml, unless differently specified. Cell numbers were counted in a hemocytometer, and cell viability was determined by the vital dye exclusion technique (0.1 % trypan blue). INTRODUCTION Prostaglandins were stored as 100% ethanolic stock solutions (2 mg/ ml) at â€”20Â°Candwere diluted to the appropriate concentrations at the Prostaglandins are known to be involved in the regulation of time of their use. Control medium contained the same concentration cell proliferation and differentiation in a large number of sys of ethanol diluent (0.02%), which did not affect cell viability or metab tems, and their action varies in relation to their molecular olism. structure, the dose, and the animal model in which their role is Duplication cycles were calculated as: log (A/B)/\og 2, where A is analyzed (1,2). PGs3 of the A, D, and E series have been shown the number of cells at the time of test, and B is the number of cells at time 0. Statistical analyses were performed using a nonparametric test to inhibit the rate of cell proliferation in several animal tumor (Wilcoxon rank sum test) for unpaired data. Data are expressed as the systems (1, 2) among which are some mouse leukemic cell lines, as L-5178-Y-R (3), L1210 leukemia (4), and WEHI-3B-D- mean Â±SD, and P values of less than 0.05 were considered significant. DNA, RNA, and Protein Synthesis. K562 cells were plated in 24-well myelomonocytic leukemia (5). PGEs and PGAs have also been Linbro plates (1 x 10* cells/ml). Cells were labeled for 24 h in RPMI shown to enhance differentiation in several leukemic cell lines, containing 10% FBS with or without prostaglandins, with [3H]thymi- such as Ml mouse myeloid leukemia (6), HL-60 human pro- dine, [3H]uridine, or [35S]methionine (10 iiCi/ml) for DNA, RNA, or myelocytic leukemia (7), and U-937 human lymphoma (8), and protein synthesis, respectively, and the radioactivity incorporated was to play a role in the control of the growth and differentiation determined as previously described (16). Briefly, labeled cells were of normal erythroid precursors (9-11). washed 3 times with PBS, dried, and dissolved in lysis buffer (0.1 M NaCl solution-0.0015 M MgClr0.01 M Tris-HCl-0.5% SDS-0.5 M In most of these systems, inhibition of cell growth was not EDTA, pH 7). Samples were collected and, after TCA precipitation, necessarily linked to stimulation of differentiation (9). the radioactivity was counted in a Beckman liquid scintillation spec We have previously demonstrated that PGs of the E and A trometer. series are potent inhibitors of two murine tumors, B16 mela Galactose Incorporation. K562 cells (1 x IO6 cells/ml) were labeled noma and the Friend virus-induced erythroleukemia (FLC), with 10 ltd of D-[6-3H]galactose per ml for 24 h in RPMI containing both in vitro and in vivo (12-15). In this last system PGAs were 10% FBS, with or without prostaglandins. Galactose incorporation into shown to be the most effective compound in both inhibiting TCA-insoluble material was measured as described in the previous cell proliferation and stimulating cell differentiation; growth paragraph. inhibition was not a prerequisite for differentiation, and PGA, PAGE. K562 cells were labeled for 24 h with [35S]methionine (10 fid/106 cells) in RPMI supplemented with 10% dialyzed FBS in the activity was found to be dependent on the phase of cell cycle presence of PGA, (4 Â¿ig/ml)orethanol diluent. [35S]Methionine-labeled and on the stage in the differentiation process (9). cells were washed 3 times with PBS and lysed in lysis buffer (2% sodium In this paper we analyzed the role of several PGs on the dodecyl sulfate-10% glycerol-0.001% bromophenol blue-0.1 M dithio- Received 3/13/86; revised 8/1/86; accepted 8/14/86. threitol-0.0625 MTris-HCl, pH 6). Radioactivity of samples was deter The costs of publication of this article were defrayed in part by the payment mined after TCA precipitation, and samples were analyzed by SDS- of page charges. This article must therefore be hereby marked advertisement in PAGE in a vertical slab gel apparatus (3% stacking gels and 7.5% accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was partially supported by a grant from the National Council of resolving gels), as previously described (17). Gels were washed, fixed in Research of Italy, P. F. "Control of Infectious Diseases," No. 8403243. 10% acetic acid-10% TCA-30% methanol, dried under vacuum, and 2To whom requests for reprints should be addressed. autoradiographed using DuPont Crune* films. Molecular weights of 3The abbreviations used are: PGs, prostaglandins; PGA,, PGA2, PGB2, PGD2, polypeptides were calculated using the following MC-methylated protein PGE,, PGE2, PGF,â€ž,prostaglandins A,, A2, B2, D2, E,, E2, F,â€ž,respectively; cAMP, cyclic AMP; dbcAMP, ./V6,O2-dibutyrylcyclic AMP; SDS, sodium dodecyl mixture: myosin (M, 200,000); phosphorylase b (M, 92,500); bovine sulfate; FBS, fetal bovine serum; PBS, phosphate-buffered saline; TCA. trichlo- serum albumin (M, 69,000); ovalbumin (M, 46,000); carbonic anhydrase roacetic acid; PAGE, polyacrylamide gel electrophoresis. (M, 30,000); and lysozyme (M, 14,000). 6073 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1986 American Association for Cancer Research. MODULATION OF KS62 CELL GROWTH BY PROSTAGLANDINS

RESULTS

Effect of Prostaglandins on the Proliferation of K562 Cells. The K562 cell line was originally established by Lozzio and Lozzio from the pleural effusion of a patient with chronic myelogenous leukemia in terminal blast crisis (18). These cells have the specific erythroid surface protein glycophorin A and can be induced to differentiate to the normoblast level and to synthesize hemoglobin (19, 20). We analyzed the effect of several PCs (PGA,, PGA2, PGB2, PGD2, PGE,, PGE2, PGF,,,) on the growth of K562 cells in suspension culture. PG treatment was started soon after plating and was not repeated to the end of the experiment. Fig. 1 shows that, at the dose used (4 Mg/ml), after 48 h PGA, and PGD2 totally blocked cell replication, while PGA2 and PGE2 partially inhibited it. After 96 h, the proliferation rate was back to normal in cells treated with PGEs, while it was still inhibited in PGA- and PGD-treated cells and slightly enhanced in PGFi,,-treated cells. These results support the hypothesis that the antiproliferative activity of prostaglandins is related to the presence of a cyclopentane ring containing a reactive a,/3-unsaturated ketone 3 4 (21, 22). At a lower dose (10~7 M) PGEs had been previously Time I days) Fig. 2. Effect of PGAi treatment on the proliferation of K562 cells. Culture reported to enhance K562 colony formation (23). conditions were the same as those described in Fig. 1. PGA, (4 fig/ml) was given at time 0 and 48 h. Control (C) received the same amount of ethanol diluent. PGAs exerted their inhibitory action without being toxic to PGA, totally blocked K562 proliferation, without altering cell viability (96% by the cells (cell viability, after 96 h, was more than 98% in both Day 5). Points, mean of triplicate cultures; bars, SD. *,P< 0.01 versus control. control and PGAi-treated cells), while PGDs were highly toxic (cell viability was decreased to 65.8% at 48 h and to less than 5% at 96 h; Fig. l ). PGA,, then, appeared to be the most active, nontoxic prostaglandin in inhibiting the growth of K.562 cells. This effect was dose dependent, with doses lower than 1 Mg/ml being ineffective, and doses above 8 ng/m\ being toxic (data not shown). As determined by radioimmunoassay, PGA, is stable in serum-free tissue culture medium at 4Â°Cfor a period of 24 h; however, since in the presence of serum at 37Â°Ca slow conver sion of PGA to PGB takes place (24), we studied the effect of repeated PGA, treatments. A second treatment after 48 h with the most active, nontoxic dose of PGA, (4 Mg/ml) resulted in a total block of cell replication (Fig. 2), without altering cell viability. Identical results were obtained when K562 cells were

48hrsCT 96hrsCT,Â»L 48 96 0 48 96 0 48 96 Time ( hours )

2*CSg1Ã¤ Fig. 3. Reversal from growth inhibition and effect of prolonged PGA, regimen. K562 cells were plated at a density of 2 x 10*cells/ml and treated with PGA, (4 >ig/ml) (first treatment). After 96 h PGA,-treated cells were washed and replated at a density of 1.8 x 10' cells/ml with (PG) or without (C) PGA, (second T,f1*TB treatment). After 96 h, these last cells were washed twice and replated at a density of 1.6 x 10' cells/ml, with (PG) or without (C) PGA, (third treatment). Points, mean of triplicate samples; bars, SD. 1OOA

T**~H treated with the same dose of a long-acting analogue of PGA, 16, 16-dimethyl-PGA2-methyl ester.4 Lack of toxicity was also shown by the ability of K562 cells to recover their growth potential after removal of PGA, from

A, A, B, D, E, E, F. A, A, B, D, E, E, F,. the culture medium (Fig. 3). K562 cells were plated at a density of 2 x 105/rnl, and PGA, l) was added soon after plating Fig. I. Effect of different prostaglandins on the growth of K562 cells. K562 cells, plated at a density of 2 x 10* cells/ml, were treated only once with several (first treatment). Treatment was not repeated for the next 96 PCs (4 /ig/ml) or control diluent (C) at the time of plating. Cell numbers were h. At this time PGA, had inhibited cell growth by 71.3% determined 48 (A) and 96 (B) h after plating, and duplication cycles were determined as described in "Materials and Methods." Columns, mean of triplicate (control = 1.29 Â±0.19 x IO6 cells/ml; PGA, = 0.37 Â±0.03 x cultures; bars, SD. *,P< 0.05 versus control. AÂ¡,PGA,; Ai, PGA2; B2, PGB2; D2, PGD2; Â£,,PGE,; Â£2.PGE2; f,â€ž,PGF,,,. ' Unpublished data. 6074 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1986 American Association for Cancer Research. MODULATION OF K562 CELL GROWTH BY PROSTAGLANDINS IO6 cells/ml). PGA,-treated cells were washed twice in FBS- SDS-polyacrylamide gel analysis of cellular polypeptides, free medium and replated at a density of 1.8 x 10s cells/ml in after [35S]methionine incorporation, is shown in Fig. 4. While either the presence (PG) or the absence of PGA, (second the overall pattern of K562 protein synthesis was not altered treatment). After 96 h cell numbers were determined. Following by PGAi treatment in these cells, PGA, specifically decreased removal of PGAi, K562 cells completely recovered their growth the synthesis of at least 2 proteins with molecular weights, potential (1.1 Â±0.1 X IO6 cells/ml), indicating that PGA, did respectively, of 92,000 and 46,000 and induced the synthesis of not affect cell viability; on the other hand, the growth of cells a polypeptide with a molecular weight of 74,000. that had received a second PGA, treatment was completely blocked (0.19 Â±0.02 x 10* cells/ml; mortality, 6.2%). These DISCUSSION last cells were washed twice and replated at a density of 1.6 x IO5 cells/ml in either the absence or the presence of PGAi The results described in this paper further emphasize the role (third treatment). After 96 h cell numbers were determined. of prostaglandins in the regulation of leukemic cell prolifera Even after removal of PGA, these cells were unable to recover tion. Among several prostaglandins tested, PGF,,, slightly en their growth potential, stayed quiescent, but vital, for the fol hanced the growth of K562 cells, and PCs of the A and D series lowing 96 h (1.63 Â±0.03 x IO5 cells/ml), and then started to drastically inhibited it. While PGD2 was cytotoxic, PGA, was die. A third treatment with PGA, was instead toxic to K562 able to totally inhibit K562 cell proliferation, without affecting cells (mortality, >90% after 96 h). These results suggest that cell viability. In fact, removal of PGA, after a 96-h treatment PGA, is able to completely block the replicative machinery of resulted in a full recovery of growth potential. However, if a these cells without altering cell viability; a prolonged (8 days) second 4-day treatment with PGA, was started, K562 cell inhibition of cell replication then causes an irreversible block proliferation appeared to be definitively impaired, and it was of cell proliferation that leads to cell death after a period of 12 not restored upon removal of PGA,. days. The fact that PGAs and PGDs are active in inhibiting cell To investigate whether the growth-inhibitory action of PGAs growth in this system further supports the hypothesis that the was mediated by cyclic AMP, the effect of an analogue of presence of a reactive a,/3-unsaturated carbonyl group in the cAMP, dibutyryl cAMP, on K562 cell growth was tested. K562 cyclopentane ring of the molecule is necessary for the antipro- cells, plated at a density of 2 x 10s cells/ml, received 0.5 mM liferative activity (21, 22). dbcAMP or control diluent soon after plating. Cell numbers The mechanism by which prostaglandins control cell repli were determined daily. Dibutyryl cAMP treatment was shown cation is presently not known. not to alter cell proliferation (after 5 days, control = 1.52 Â± It has been hypothesized that the growth-regulatory action of 0.06 x IO6cells/ml; dbcAMP = 1.39 Â±0.08 x IO6cells/ml). PCs could be mediated by cyclic AMP (1, 25). Even though Effect of PGA, on Macromolecular Synthesis of K562 Cells. this possibility cannot be ruled out, the fact that PGA, is acting The effect of PGAi on DNA, RNA, and protein synthesis of via a cAMP-independent mechanism, in our system, is sug K562 cells was determined. K562 cells were plated at a density gested by two observations: (a) PGEi, which is usually active in of 1 X IO6 cells/ml in RPMI containing PGA,, at the growth- increasing adenylate cyclase activity, does not affect cell growth inhibitory dose (4 /ig/ml), or control diluent. The incorporation in these cells; and (b) treatment of K562 cells with dibutyryl of radiolabeled precursors for DNA, RNA, or protein synthesis cyclic AMP up to a concentration of 0.5 mM did not inhibit into acid-insoluble material was determined 24 h later, as cell proliferation. Moreover, at a lower dose (10~7 M), both described in "Materials and Methods." As shown in Table 1, a PGEs and dibutyryl cyclic AMP had been previously reported 24-h treatment with PGA,, while it inhibited cell proliferation, to actually enhance K562 colony formation (23). surprisingly did not decrease DNA synthesis. RNA synthesis Preliminary results indicate that, in K562 cells, the inhibitory was not affected, while protein synthesis was inhibited by action of PGA, was not dependent, as in FLC cells, on the 38.0%. Inhibition of protein synthesis was specific for PGAs, phase of the cell cycle and was not associated with stimulation while PGEs, PGBs, and PGFs had no effect, and PGDs were of erythroid differentiation, since PGA, treatment did not pro toxic (data not shown). PGA, treatment also caused a 32.3% duce an increase in the number of benzidine-positive (hemoglo inhibition of protein glycosylation, as measured by D-[6- bin-containing) cells. 3H]galactose incorporation into TCA-insoluble material. We have shown that the PGA,-induced block of K562 cell We have previously shown that some actions of PGAs, as replication is not due directly to suppression of DNA synthesis. described in the following section, are related to alterations of In fact, a 24-h treatment with PGA, did not alter DNA and the protein synthesis machinery. We then have studied the RNA synthesis, but partially inhibited protein synthesis and electrophoretic patterns of proteins of K562 cells treated or not glycosylation. treated with PGA,. We have previously reported that PGA, induces the synthesis of a new protein in African green monkey kidney cells (26), as Table I Effect of PGA, on macromolecular synthesis ofKS62 cells K562 cells (1 x IO6cells/ml) were labeled for 24 h with |3H]thymidine, [3HJ- well as the synthesis of two enzymes, a protein kinase and the uridine, or [35S]methionine (10 ^Ci/ml) for DNA, RNA, or protein synthesis, 2,5A-synthetase, whose induction is also stimulated by inter- respectively, in the presence of PGAi (4 /jg/ml) or control diluent. Glycosylation feron, in mouse L-fibroblasts (27). We have also shown that was measured by [3HJgalactose incorporation, as described in "Materials and Methods." PGA, is a potent antiviral agent (28) and is able to inhibit the synthesis of some specific viral proteins in vesicular stomatitis xControl1 of in virus- and vaccinia virus-infected mouse fibroblasts (29-31). IncorporationofThymidine hibition38.0 We have now also demonstrated that the antiproliferative action 12.3 Â±27.5" Â±2.2 of PGA, is associated with alteration of protein synthesis. PGA, Uridine 53.4 Â±2.0 54.6 Â±2.1 treatment specifically decreased the production of two polypep Methionine 119.6 Â±9.4 74.1 Â±0.4* Galactosecpm 50.1 Â±0.1IO3PGA,133.133.9 Â±0.3'% 32.3 tides in K562 cells, while it stimulated the synthesis of a M, Â°Mean Â±SD (cpm x 103/10' cells) of at least duplicate samples. 74,000 protein. */><0.05. The possibility that this PG-induced protein could be in- 6075 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1986 American Association for Cancer Research. MODULATION OF K562 CELL GROWTH BY PROSTAGLANDINS

92 K

-46K

â€¢Â«= Fig. 4. Effect of PGAi on protein synthesis. K562 cells were labeled for 24 h with [3!S]methionine (10 fiCi/10' cells) in the presence of PGA, (4 ng/ml) or ethanol diluent. Electrophoretic patterns of radiolabeled proteins are shown in b. White-pointed arrow indicates the M, 74,000 protein induced by treatment with PGA,. Black-pointed arrows indicate the M, 92,000 and 46,000 proteins, whose synthesis is decreased by PGA,, a, densitometric analysis of control (C) and PGA] (PG) autoradiographic patterns in ft. The direction of migration is indicated by the arrow at the bottom of the figure.

Moore, M. A. S. G-CSF: its relationship to leukemia differentiation-inducing volved in the control of K562 cell replication is presently under activity and other hemopoietic regulators. J. Cell Physiol., / (Suppl.): 53- study. Preliminary data have demonstrated that other prosta- 64, 1982. glandins that do not block K562 cell replication (PGE,, PGB2, Honma, Y., Kasukabe, T., Hozumi, M., and Koshihara, Y. Regulation of prostaglandin synthesis during differentiation of cultured mouse myeloid and PCF,,,) did not induce the synthesis of the M, 74,000 leukemia cells. J. Cell Physiol., 104: 349-357, 1980. protein. Olsson, I. L., Breitman, T. R., and Gallo, R. C. Priming of human myeloid leukemia cell lines HL-60 and U-937 with retinoic acid for differentiation The synthesis of a polypeptide of the same molecular weight effects of cyclic adenosine 3':5'-monophosphate-inducing agents and a T- is also induced by PGA, treatment in a clone of Friend erythro- lymphocyte-derived differentiation factor. Cancer Res., 42:3928-3933,1982. leukemic cells (FF 16) that is particularly sensitive to the anti- Olsson, I. L., and Breitman, T. R. Induction of differentiation of the human proliferative action of PGAj.5 histiocytic lymphoma cell line U-937 by retinoic acid and cyclic adenosine 3':5'-monophosphate-inducing agents. Cancer Res., 42: 3924-3927, 1982. The results strongly support the concept that PGs containing Santoro, M. G., and Jaffe, B. M. Prostaglandins and differentiation of Friend a reactive Â«,,0-unsaturated carbonyl group in the cyclopentane erythroleukemia cells. In: S. HammarstrÃ¶m (ed.), Prostaglandins and Tumor Cell Proliferation and Differentiation. La Hague: Martinus Nijhoff, in press, ring are potential antineoplastic agents. They also emphasize 1986. the importance of the length and schedule of treatment in order 10. Cline, M. J., and Golde, D. W. Cellular interactions in haematopoiesis. to obtain maximal antiproliferative effect and suggest that the Nature (Lond.), 277: 177-181, 1979. De Gowin, R. L., and Gibson, D. P. Prostaglandin-mediated enhancement growth-inhibitory action of PGAi is related to alterations of of erythroid colonies by marrow stromal cells. Exp. Hematol., 9: 274-280, protein synthesis. 1981. Santoro, M. G., Philpott, G. W., and Jaffe, B. M. Inhibition of tumor growth in vivo and in vitro by prostaglandin E. Nature (Lond.), 263: 777-779,1976. REFERENCES Santoro, M. G., Benedetto, A., and Jaffe, B. M. Prostaglandin A, induces differentiation in Friend erythroleukemia cells. Prostaglandins, 17:719-727, 1. Jaffe, B. 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6077 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1986 American Association for Cancer Research. Modulation of the Growth of a Human Erythroleukemic Cell Line (K562) by Prostaglandins: Antiproliferative Action of Prostaglandin A

M. Gabriella Santoro, Antonella Crisari, Arrigo Benedetto, et al.

Cancer Res 1986;46:6073-6077.

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