Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1998 Dec 15;336(Pt 3):569–576. doi: 10.1042/bj3360569

Anti-cancer-prostaglandin-induced cell-cycle arrest and its modulation by an inhibitor of the ATP-dependent glutathione S-conjugate export pump (GS-X pump).

T Ishikawa 1, K Akimaru 1, M Nakanishi 1, K Tomokiyo 1, K Furuta 1, M Suzuki 1, R Noyori 1
PMCID: PMC1219906  PMID: 9841867

Abstract

The A and J series of prostaglandins (PGs) accumulate in the nuclei to suppress the proliferation of cancer cells. Here we report that Delta7-PGA1 methyl ester, a synthetic anti-cancer PG, increased the level of mRNA for the cyclin-dependent kinase inhibitor p21 in human leukaemia HL-60 cells. The induction of p21 was associated with the accumulation of hypophosphorylated retinoblastoma protein (pRB) and the suppression of c-myc gene expression. Since the p53 gene is deleted in HL-60 cells, the anti-cancer PG is suggested to inhibit cancer cell growth by inducing p21 via a p53-independent pathway. Unlike HL-60 cells, cisplatin-resistant HL-60/R-CP cells were insensitive to Delta7-PGA1 methyl ester. While c-myc expression was transiently suppressed, neither G1 arrest nor hypophosphorylation of pRB was observed with the anti-cancer PG. Plasma membrane vesicles from HL-60/R-CP cells showed an enhanced level of GS-X pump (ATP-dependent glutathione S-conjugate export pump) activity towards the glutathione S-conjugate of Delta7-PGA1 methyl ester (Km 110 nM). GIF-0019 ¿N-carbomethoxy-S-[5-(4-benzoylphenyl)pentyl]glutathione dimethyl ester¿, a specific inhibitor of the GS-X pump, dose-dependently enhanced the cellular sensitivity of HL-60/R-CP cells to Delta7-PGA1 methyl ester and induced G1 arrest. The GS-X pump is suggested to play a pivotal role in modulating the biological action of the anti-cancer PG.

Full Text

The Full Text of this article is available as a PDF (225.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akimaru K., Nakanishi M., Suzuki M., Furuta K., Noyori R., Ishikawa T. Cell growth inhibition by antitumor prostaglandin and its modulation by MRP/GS-X pump. Adv Exp Med Biol. 1997;407:387–391. doi: 10.1007/978-1-4899-1813-0_58. [DOI] [PubMed] [Google Scholar]
  2. Atsmon J., Freeman M. L., Meredith M. J., Sweetman B. J., Roberts L. J., 2nd Conjugation of 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 with intracellular glutathione and enhancement of its antiproliferative activity by glutathione depletion. Cancer Res. 1990 Mar 15;50(6):1879–1885. [PubMed] [Google Scholar]
  3. Bulter J., Spielberg S. P., Schulman J. D. Reduction of disulfide-containing amines amino acids, and small peptides. Anal Biochem. 1976 Oct;75(2):674–675. doi: 10.1016/0003-2697(76)90129-9. [DOI] [PubMed] [Google Scholar]
  4. Büchler M., König J., Brom M., Kartenbeck J., Spring H., Horie T., Keppler D. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J Biol Chem. 1996 Jun 21;271(25):15091–15098. doi: 10.1074/jbc.271.25.15091. [DOI] [PubMed] [Google Scholar]
  5. Cagen L. M., Pisano J. J., Ketley J. N., Habig W. H., Jakoby W. B. The conjugation of prostaglandin A1 and glutathione catalyzed by homogeneous glutathione s-transferases from human and rat liver. Biochim Biophys Acta. 1975 Jul 22;398(1):205–208. doi: 10.1016/0005-2760(75)90184-8. [DOI] [PubMed] [Google Scholar]
  6. Cole S. P., Bhardwaj G., Gerlach J. H., Mackie J. E., Grant C. E., Almquist K. C., Stewart A. J., Kurz E. U., Duncan A. M., Deeley R. G. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992 Dec 4;258(5088):1650–1654. doi: 10.1126/science.1360704. [DOI] [PubMed] [Google Scholar]
  7. Elledge S. J., Harper J. W. Cdk inhibitors: on the threshold of checkpoints and development. Curr Opin Cell Biol. 1994 Dec;6(6):847–852. doi: 10.1016/0955-0674(94)90055-8. [DOI] [PubMed] [Google Scholar]
  8. Evan G. I., Littlewood T. D. The role of c-myc in cell growth. Curr Opin Genet Dev. 1993 Feb;3(1):44–49. doi: 10.1016/s0959-437x(05)80339-9. [DOI] [PubMed] [Google Scholar]
  9. Evers R., Cnubben N. H., Wijnholds J., van Deemter L., van Bladeren P. J., Borst P. Transport of glutathione prostaglandin A conjugates by the multidrug resistance protein 1. FEBS Lett. 1997 Dec 8;419(1):112–116. doi: 10.1016/s0014-5793(97)01442-7. [DOI] [PubMed] [Google Scholar]
  10. Ewen M. E., Sluss H. K., Sherr C. J., Matsushime H., Kato J., Livingston D. M. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993 May 7;73(3):487–497. doi: 10.1016/0092-8674(93)90136-e. [DOI] [PubMed] [Google Scholar]
  11. Gomi A., Shinoda S., Masuzawa T., Ishikawa T., Kuo M. T. Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells. Cancer Res. 1997 Dec 1;57(23):5292–5299. [PubMed] [Google Scholar]
  12. Gorospe M., Holbrook N. J. Role of p21 in prostaglandin A2-mediated cellular arrest and death. Cancer Res. 1996 Feb 1;56(3):475–479. [PubMed] [Google Scholar]
  13. Gorospe M., Liu Y., Xu Q., Chrest F. J., Holbrook N. J. Inhibition of G1 cyclin-dependent kinase activity during growth arrest of human breast carcinoma cells by prostaglandin A2. Mol Cell Biol. 1996 Mar;16(3):762–770. doi: 10.1128/mcb.16.3.762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  15. Hayaishi O. Molecular mechanisms of sleep-wake regulation: roles of prostaglandins D2 and E2. FASEB J. 1991 Aug;5(11):2575–2581. [PubMed] [Google Scholar]
  16. Hiebert S. W., Lipp M., Nevins J. R. E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor. Proc Natl Acad Sci U S A. 1989 May;86(10):3594–3598. doi: 10.1073/pnas.86.10.3594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hitomi M., Shu J., Strom D., Hiebert S. W., Harter M. L., Stacey D. W. Prostaglandin A2 blocks the activation of G1 phase cyclin-dependent kinase without altering mitogen-activated protein kinase stimulation. J Biol Chem. 1996 Apr 19;271(16):9376–9383. doi: 10.1074/jbc.271.16.9376. [DOI] [PubMed] [Google Scholar]
  18. Honn K. V., Marnett L. J. Requirement of a reactive alpha, beta-unsaturated carbonyl for inhibition of tumor growth and induction of differentiation by "A" series prostaglandins. Biochem Biophys Res Commun. 1985 May 31;129(1):34–40. doi: 10.1016/0006-291x(85)91398-1. [DOI] [PubMed] [Google Scholar]
  19. Hunter T., Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. doi: 10.1016/0092-8674(94)90543-6. [DOI] [PubMed] [Google Scholar]
  20. Ishikawa T. ATP/Mg2+-dependent cardiac transport system for glutathione S-conjugates. A study using rat heart sarcolemma vesicles. J Biol Chem. 1989 Oct 15;264(29):17343–17348. [PubMed] [Google Scholar]
  21. Ishikawa T., Bao J. J., Yamane Y., Akimaru K., Frindrich K., Wright C. D., Kuo M. T. Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem. 1996 Jun 21;271(25):14981–14988. doi: 10.1074/jbc.271.25.14981. [DOI] [PubMed] [Google Scholar]
  22. Ishikawa T., Li Z. S., Lu Y. P., Rea P. A. The GS-X pump in plant, yeast, and animal cells: structure, function, and gene expression. Biosci Rep. 1997 Apr;17(2):189–207. doi: 10.1023/a:1027385513483. [DOI] [PubMed] [Google Scholar]
  23. Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci. 1992 Nov;17(11):463–468. doi: 10.1016/0968-0004(92)90489-v. [DOI] [PubMed] [Google Scholar]
  24. Ishikawa T., Wright C. D., Ishizuka H. GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. J Biol Chem. 1994 Nov 18;269(46):29085–29093. [PubMed] [Google Scholar]
  25. Ito K., Suzuki H., Hirohashi T., Kume K., Shimizu T., Sugiyama Y. Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol. 1997 Jan;272(1 Pt 1):G16–G22. doi: 10.1152/ajpgi.1997.272.1.G16. [DOI] [PubMed] [Google Scholar]
  26. Johnson M., Dimitrov D., Vojta P. J., Barrett J. C., Noda A., Pereira-Smith O. M., Smith J. R. Evidence for a p53-independent pathway for upregulation of SDI1/CIP1/WAF1/p21 RNA in human cells. Mol Carcinog. 1994 Oct;11(2):59–64. doi: 10.1002/mc.2940110202. [DOI] [PubMed] [Google Scholar]
  27. Kikuchi Y., Kita T., Miyauchi M., Hirata J., Sasa H., Nagata I., Fukushima M. Adjuvant effects of antineoplastic prostaglandins to cisplatin in nude mice bearing human ovarian cancer cells. J Cancer Res Clin Oncol. 1992;118(6):453–457. doi: 10.1007/BF01629429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kool M., de Haas M., Scheffer G. L., Scheper R. J., van Eijk M. J., Juijn J. A., Baas F., Borst P. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 1997 Aug 15;57(16):3537–3547. [PubMed] [Google Scholar]
  29. Kuo M. T., Bao J. J., Curley S. A., Ikeguchi M., Johnston D. A., Ishikawa T. Frequent coordinated overexpression of the MRP/GS-X pump and gamma-glutamylcysteine synthetase genes in human colorectal cancers. Cancer Res. 1996 Aug 15;56(16):3642–3644. [PubMed] [Google Scholar]
  30. Leier I., Jedlitschky G., Buchholz U., Cole S. P., Deeley R. G., Keppler D. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem. 1994 Nov 11;269(45):27807–27810. [PubMed] [Google Scholar]
  31. Morgan D. O. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131–134. doi: 10.1038/374131a0. [DOI] [PubMed] [Google Scholar]
  32. Müller M., Meijer C., Zaman G. J., Borst P., Scheper R. J., Mulder N. H., de Vries E. G., Jansen P. L. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):13033–13037. doi: 10.1073/pnas.91.26.13033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nakanishi M., Adami G. R., Robetorye R. S., Noda A., Venable S. F., Dimitrov D., Pereira-Smith O. M., Smith J. R. Exit from G0 and entry into the cell cycle of cells expressing p21Sdi1 antisense RNA. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4352–4356. doi: 10.1073/pnas.92.10.4352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nakanishi M., Robetorye R. S., Adami G. R., Pereira-Smith O. M., Smith J. R. Identification of the active region of the DNA synthesis inhibitory gene p21Sdi1/CIP1/WAF1. EMBO J. 1995 Feb 1;14(3):555–563. doi: 10.1002/j.1460-2075.1995.tb07031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nakanishi M., Robetorye R. S., Pereira-Smith O. M., Smith J. R. The C-terminal region of p21SDI1/WAF1/CIP1 is involved in proliferating cell nuclear antigen binding but does not appear to be required for growth inhibition. J Biol Chem. 1995 Jul 21;270(29):17060–17063. doi: 10.1074/jbc.270.29.17060. [DOI] [PubMed] [Google Scholar]
  36. Narumiya S., Ohno K., Fujiwara M., Fukushima M. Site and mechanism of growth inhibition by prostaglandins. II. Temperature-dependent transfer of a cyclopentenone prostaglandin to nuclei. J Pharmacol Exp Ther. 1986 Nov;239(2):506–511. [PubMed] [Google Scholar]
  37. Narumiya S., Ohno K., Fukushima M., Fujiwara M. Site and mechanism of growth inhibition by prostaglandins. III. Distribution and binding of prostaglandin A2 and delta 12-prostaglandin J2 in nuclei. J Pharmacol Exp Ther. 1987 Jul;242(1):306–311. [PubMed] [Google Scholar]
  38. Nevins J. R. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science. 1992 Oct 16;258(5081):424–429. doi: 10.1126/science.1411535. [DOI] [PubMed] [Google Scholar]
  39. Noyori R., Suzuki M. Organic synthesis of prostaglandins: advancing biology. Science. 1993 Jan 1;259(5091):44–45. doi: 10.1126/science.8418493. [DOI] [PubMed] [Google Scholar]
  40. Ohno K., Sakai T., Fukushima M., Narumiya S., Fujiwara M. Site and mechanism of growth inhibition by prostaglandins. IV. Effect of cyclopentenone prostaglandins on cell cycle progression of G1-enriched HeLa S3 cells. J Pharmacol Exp Ther. 1988 Apr;245(1):294–298. [PubMed] [Google Scholar]
  41. Oswald F., Lovec H., Möröy T., Lipp M. E2F-dependent regulation of human MYC: trans-activation by cyclins D1 and A overrides tumour suppressor protein functions. Oncogene. 1994 Jul;9(7):2029–2036. [PubMed] [Google Scholar]
  42. Paulusma C. C., Bosma P. J., Zaman G. J., Bakker C. T., Otter M., Scheffer G. L., Scheper R. J., Borst P., Oude Elferink R. P. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science. 1996 Feb 23;271(5252):1126–1128. doi: 10.1126/science.271.5252.1126. [DOI] [PubMed] [Google Scholar]
  43. Santoro M. G., Benedetto A., Carruba G., Garaci E., Jaffe B. M. Prostaglandin A compounds as antiviral agents. Science. 1980 Aug 29;209(4460):1032–1034. doi: 10.1126/science.6157190. [DOI] [PubMed] [Google Scholar]
  44. Song W. C., Brash A. R. Purification of an allene oxide synthase and identification of the enzyme as a cytochrome P-450. Science. 1991 Aug 16;253(5021):781–784. doi: 10.1126/science.1876834. [DOI] [PubMed] [Google Scholar]
  45. Toyoshima H., Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67–74. doi: 10.1016/0092-8674(94)90573-8. [DOI] [PubMed] [Google Scholar]
  46. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  47. Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. doi: 10.1038/366701a0. [DOI] [PubMed] [Google Scholar]
  48. Zaman G. J., Flens M. J., van Leusden M. R., de Haas M., Mülder H. S., Lankelma J., Pinedo H. M., Scheper R. J., Baas F., Broxterman H. J. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8822–8826. doi: 10.1073/pnas.91.19.8822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. el-Deiry W. S., Harper J. W., O'Connor P. M., Velculescu V. E., Canman C. E., Jackman J., Pietenpol J. A., Burrell M., Hill D. E., Wang Y. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed] [Google Scholar]
  50. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES