Home LiteratureArticle Details
PMID: 12192599 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

Exposure of human breast cancer cells to the anti-inflammatory agent indomethacin alters choline phospholipid metabolites and Nm23 expression.

Neoplasia (New York, N.Y.) ·Vol. 4 ·No. 5 ·2002-00-00 ·Pages 409-16

Natarajan K, Mori N, Artemov D, Bhujwalla ZM

Abstract

We previously observed that changes in choline phospholipids of two malignant human mammary epithelial cells (HMECs) following treatment with a high dose of the cyclooxygenase (COX) inhibitor, indomethacin, mimicked changes following transfection with a metastasis suppressor gene, nm23. The similarity between response to indomethacin and nm23 transfection led us to 1) expand our (1)H NMR spectroscopy study of indomethacin treatment by determining the response at two doses for two nonmalignant and three malignant HMECs, 2) investigate COX-1 and COX-2 levels in HMECs and their relationship with choline phosholipid metabolites, and 3) determine changes in Nm23 expression following treatment with indomethacin. All HMECs exhibited a significant change in choline phospholipids following treatment with 300 microM indomethacin. At the lower dose of 50 microM, only nonmalignant HMECs and the estrogen-dependent malignant cell line, MCF-7, responded. COX-1 levels were significantly higher in malignant HMECs than in nonmalignant HMECs. A significant increase in Nm23 expression following 300 microM indomethacin was detected in MCF-12A and MCF-7 cells but not in MDA-MB-231 and MDA-MB-435 cells. These results suggest that COX-1 expression and its inhibition play a role in the choline phospholipid metabolism of HMECs, and the effect of indomethacin on HMECs may be mediated, in part, through upregulation of nm23.

MeSH Terms
Anti-Inflammatory Agents, Non-Steroidal/pharmacology Blotting, Western Breast Neoplasms/drug therapy,metabolism Cell Division/drug effects Choline/metabolism Cyclooxygenase 1 Cyclooxygenase 2 Epithelial Cells/metabolism Female Glycerylphosphorylcholine/metabolism Humans Indomethacin/pharmacology Isoenzymes/metabolism Magnetic Resonance Spectroscopy Membrane Proteins Monomeric GTP-Binding Proteins/metabolism NM23 Nucleoside Diphosphate Kinases Nucleoside-Diphosphate Kinase Phosphorylcholine/metabolism Prostaglandin-Endoperoxide Synthases/metabolism Transcription Factors/metabolism Tumor Cells, Cultured
Chemicals
Anti-Inflammatory Agents, Non-Steroidal Isoenzymes Membrane Proteins NM23 Nucleoside Diphosphate Kinases Transcription Factors Phosphorylcholine Glycerylphosphorylcholine Cyclooxygenase 1 Cyclooxygenase 2 PTGS1 protein, human PTGS2 protein, human Prostaglandin-Endoperoxide Synthases NME1 protein, human Nucleoside-Diphosphate Kinase Monomeric GTP-Binding Proteins Choline Indomethacin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Natarajan Kshama
Department of Radiology, MR Oncology Section, Division of MR Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mori Noriko
Artemov Dmitri
Bhujwalla Zaver M
References (63)
63 references, click to expand
  1. Tumour phospholipid metabolism.
    NMR Biomed. 1999 Nov;12(7):413-39 PMID: 10654290
  2. Indomethacin potentiates the induction of HL60 differentiation to neutrophils, by retinoic acid and granulocyte colony-stimulating factor, and to monocytes, by vitamin D3.
    Leukemia. 1994 Apr;8(4):595-604 PMID: 7512172
  3. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action.
    Eur J Cancer. 2000 Mar;36(5):664-74 PMID: 10738133
  4. Phospholipid profiles of invasive human breast cancer cells are altered towards a less invasive phospholipid profile by the anti-inflammatory agent indomethacin.
    Adv Enzyme Regul. 2000;40:271-84 PMID: 10828355
  5. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice.
    Cancer Res. 2000 Sep 1;60(17):4705-8 PMID: 10987272
  6. Metastasis-suppressor genes: a review and perspective on an emerging field.
    J Natl Cancer Inst. 2000 Nov 1;92(21):1717-30 PMID: 11058615
  7. Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
    Nature. 1970 Aug 15;227(5259):680-5 PMID: 5432063
  8. Eicosanoids and metastasis: experimental aspects in Lewis lung carcinoma.
    Cancer Biochem Biophys. 1986 Dec;9(1):97-104 PMID: 3815323
  9. Altered expression of NM23, a gene associated with low tumor metastatic potential, during adenovirus 2 Ela inhibition of experimental metastasis.
    Cancer Res. 1988 Nov 15;48(22):6550-4 PMID: 2460224
  10. The role of eicosanoids in tumor metastasis.
    Prostaglandins Leukot Essent Fatty Acids. 1988;34(3):229-37 PMID: 3065787
  11. Long wave ultraviolet radiation stimulates arachidonic acid release and cyclooxygenase activity in mammalian cells in culture.
    Photochem Photobiol. 1989 Apr;49(4):423-30 PMID: 2498914
  12. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review.
    Cancer Res. 1989 Dec 1;49(23):6449-65 PMID: 2684393
  13. Phospholipases in biology and medicine.
    Clin Biochem. 1990 Oct;23(5):349-70 PMID: 2253331
  14. Serum immunoreactive pancreatic phospholipase A2 in patients with various malignant tumors.
    Enzyme. 1990;43(2):80-8 PMID: 1702053
  15. Expression of the antimetastatic gene nm23 in human breast cancer: an association with good prognosis.
    J Natl Cancer Inst. 1991 Feb 20;83(4):281-5 PMID: 1994057
  16. The phosphocholine and glycerophosphocholine content of an oestrogen-sensitive rat mammary tumour correlates strongly with growth rate.
    Br J Cancer. 1991 Nov;64(5):821-6 PMID: 1931601
  17. Characterization of epithelial phenotypes in mortal and immortal human breast cells.
    Int J Cancer. 1992 Feb 1;50(3):463-73 PMID: 1370949
  18. Eicosanoids in breast cancer patients before and after mastectomy.
    Prostaglandins Leukot Essent Fatty Acids. 1992 Apr;45(4):319-27 PMID: 1603822
  19. Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide.
    J Biol Chem. 1992 Dec 25;267(36):25934-8 PMID: 1464605
  20. An assessment of 31P MRS as a method of measuring pH in rat tumours.
    NMR Biomed. 1992 Nov-Dec;5(6):351-9 PMID: 1489671
  21. Inhibition of cell motility after nm23 transfection of human and murine tumor cells.
    Cancer Res. 1993 May 1;53(9):1971-3 PMID: 8481897
  22. Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity.
    Oncogene. 1993 Sep;8(9):2325-33 PMID: 8395676
  23. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester.
    J Clin Invest. 1994 Feb;93(2):493-8 PMID: 8113389
  24. Metabolic consequences of a reversed pH gradient in rat tumors.
    Cancer Res. 1994 Aug 1;54(15):4011-6 PMID: 8033132
  25. 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate.
    Am J Physiol. 1994 Jul;267(1 Pt 1):C195-203 PMID: 8048479
  26. Growth, differentiation, and transformation of human mammary epithelial cells in culture.
    Cancer Treat Res. 1994;71:29-48 PMID: 7946953
  27. Phospholipases A2 in ras-transformed and immortalized human mammary epithelial cells.
    Cancer Lett. 1994 Oct 28;86(1):11-21 PMID: 7954346
  28. Effects of cytokine-mediated modulation of nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells.
    Int J Cancer. 1995 Jan 17;60(2):204-10 PMID: 7829217
  29. The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma.
    Oncology. 1995 Jul-Aug;52(4):265-71 PMID: 7777237
  30. Evidence for separate mechanisms of antiproliferative action of indomethacin and prostaglandin on MCF-7 breast cancer cells.
    Life Sci. 1995;57(12):1233-40 PMID: 7674812
  31. Pyruvate utilization, phosphocholine and adenosine triphosphate (ATP) are markers of human breast tumor progression: a 31P- and 13C-nuclear magnetic resonance (NMR) spectroscopy study.
    Cancer Res. 1995 Nov 15;55(22):5140-5 PMID: 7585561
  32. Early increase in choline kinase activity upon induction of the H-ras oncogene in mouse fibroblast cell lines.
    Arch Biochem Biophys. 1995 Nov 10;323(2):313-22 PMID: 7487093
  33. Variations in energy and phospholipid metabolism in normal and cancer human mammary epithelial cells.
    Anticancer Res. 1996 May-Jun;16(3B):1381-8 PMID: 8694505
  34. Dietary linoleic acid-stimulated human breast cancer cell growth and metastasis in nude mice and their suppression by indomethacin, a cyclooxygenase inhibitor.
    Nutr Cancer. 1996;25(3):231-40 PMID: 8771566
  35. Immortalization and transformation are associated with specific alterations in choline metabolism.
    Cancer Res. 1996 Oct 15;56(20):4630-5 PMID: 8840976
  36. Identification of arachidonic acid pathways required for the invasive and metastatic activity of malignant tumor cells.
    Prostaglandins. 1996 Jan;51(1):1-17 PMID: 8900440
  37. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2.
    J Biol Chem. 1996 Dec 27;271(52):33157-60 PMID: 8969167
  38. Tumorigenic transformation of immortalized ECV endothelial cells by cyclooxygenase-1 overexpression.
    J Biol Chem. 1997 Aug 22;272(34):21455-60 PMID: 9261162
  39. A human cell line from a pleural effusion derived from a breast carcinoma.
    J Natl Cancer Inst. 1973 Nov;51(5):1409-16 PMID: 4357757
  40. Indomethacin serum concentrations in man. Effects of dosage, food, and antacid.
    Ann Rheum Dis. 1976 Aug;35(4):333-8 PMID: 970990
  41. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications.
    Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350-4 PMID: 388439
  42. Comparative evaluation of carprofen and indomethacin in rheumatoid patients.
    Int J Clin Pharmacol Ther Toxicol. 1980 Nov;18(11):482-7 PMID: 7009441
  43. Prostaglandins in breast cancer: relationship to disease stage and hormone status.
    Br J Cancer. 1983 Nov;48(5):689-96 PMID: 6416285
  44. The tumour bed effect: a cell kinetic and histological investigation of tumours growing in irradiated mouse skin.
    Br J Radiol. 1985 May;58(689):443-51 PMID: 4063693
  45. Fine-needle biopsy specimens of benign breast lesions distinguished from invasive cancer ex vivo with proton MR spectroscopy.
    Radiology. 1997 Sep;204(3):661-6 PMID: 9280241
  46. Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis.
    Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):681-6 PMID: 9435252
  47. Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer.
    J Natl Cancer Inst. 1998 Mar 18;90(6):455-60 PMID: 9521170
  48. Cyclooxygenase regulates angiogenesis induced by colon cancer cells.
    Cell. 1998 May 29;93(5):705-16 PMID: 9630216
  49. TNF-induced modulations of phospholipid metabolism in human breast cancer cells.
    Biochim Biophys Acta. 1998 Jun 15;1392(2-3):217-32 PMID: 9630635
  50. Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells.
    Cancer Res. 1999 Jan 1;59(1):80-4 PMID: 9892190
  51. NM23-NDP kinase.
    Int J Biochem Cell Biol. 1998 Dec;30(12):1291-5 PMID: 9924799
  52. Relationship of arachidonic acid metabolizing enzyme expression in epithelial cancer cell lines to the growth effect of selective biochemical inhibitors.
    Cancer Res. 1999 May 1;59(9):2223-8 PMID: 10232612
  53. Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro.
    Magn Reson Med. 1999 May;41(5):897-903 PMID: 10332871
  54. Increased choline kinase activity and elevated phosphocholine levels in human colon cancer.
    Jpn J Cancer Res. 1999 Apr;90(4):419-24 PMID: 10363580
  55. Cyclooxygenase-1 and -2 isoenzymes.
    Int J Biochem Cell Biol. 1999 May;31(5):551-7 PMID: 10399316
  56. The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines.
    Int J Oncol. 1999 Aug;15(2):267-70 PMID: 10402236
  57. Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition.
    J Biol Chem. 1999 Aug 13;274(33):22903-6 PMID: 10438452
  58. Characterization of neoplastic and normal human breast tissues with in vivo (1)H MR spectroscopy.
    J Magn Reson Imaging. 1999 Aug;10(2):159-64 PMID: 10441019
  59. Malignant transformation and antineoplastic actions of nonsteroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-null embryo fibroblasts.
    J Exp Med. 1999 Aug 16;190(4):451-59 PMID: 10449516
  60. Metabolite composition in breast tumors examined by proton nuclear magnetic resonance spectroscopy.
    Anticancer Res. 1999 May-Jun;19(3A):1737-46 PMID: 10470108
  61. Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells.
    Cancer Res. 1999 Oct 1;59(19):5047-53 PMID: 10519422
  62. Protein measurement with the Folin phenol reagent.
    J Biol Chem. 1951 Nov;193(1):265-75 PMID: 14907713
  63. Cyclooxygenase-deficient mice. A summary of their characteristics and susceptibilities to inflammation and carcinogenesis.
    Ann N Y Acad Sci. 1999;889:52-61 PMID: 10668482
Article Info
Journal
Neoplasia (New York, N.Y.)
Abbr.
Neoplasia
ISSN
1522-8002
DOI
10.1038/sj.neo.7900252
Published
2002-00-00
Pages
409-16
Language
English
Region
United States
NLM ID
100886622
PMCID
PMC1679817
Subset
IM
Grants
NCI NIH HHS · R01 CA082337 · United States
NCI NIH HHS · 1R01 CA82337 · United States
External Links
PubMed source DOI: 10.1038/sj.neo.7900252 PMC Full Text
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2