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. 2001 Mar;84(6):802–807. doi: 10.1054/bjoc.2000.1648

Decrease of breast cancer cell invasiveness by sodium phenylacetate (NaPa) is associated with an increased expression of adhesive molecules

M Vasse 1, D Thibout 2, J Paysant 1, E Legrand 1, C Soria 1,3, M Crépin 2
PMCID: PMC2363819  PMID: 11259095

Abstract

Sodium phenylacetate (NaPa), a non-toxic phenylalanine metabolite, has been shown to induce in vivo and in vitro cytostatic and antiproliferative effects on various cell types. In this work, we analysed the effect of NaPa on the invasiveness of breast cancer cell (MDA-MB-231, MCF-7 and MCF-7 ras). Using the highly invasive breast cancer cell line MDA-MB-231, we demonstrated that an 18-hour incubation with NaPa strongly inhibits the cell invasiveness through Matrigel (86% inhibition at 20 mM of NaPa). As cell invasiveness is greatly influenced by the expression of urokinase (u-PA) and its cell surface receptor (u-PAR) as well as the secretion of matrix metalloproteinases (MMP), we tested the effect of NaPa on these parameters. An 18-hour incubation with NaPa did not modify u-PA expression, either on MDA-MB-231 or on MCF-7 and MCF-7 ras cell lines, and induced a small u-PA decrease after 3 days of treatment of MDA-MB-321 with NaPa. In contrast, an 18 h incubation of MDA-MB-231 increased the expression of u-PAR and the secretion of MMP-9. As u-PAR is a ligand for vitronectin, a composant of the extracellular matrix, these data could explain the increased adhesion of MDA-MB-231 to vitronectin, while cell adhesivity of MCF-7 and MCF-7 ras was unmodified by NaPa treatment. NaPa induced also an increased expression of both Lymphocyte Function-Associated-1 (LFA-1) and Intercellular Adhesion Molecule-1 (ICAM-1), which was obvious from 18 hour incubation with NaPa for the MDA-MB-231 cells, but was delayed (3 days) for MCF-7 and MCF-7 ras. Only neutralizing antibodies against LFA-1 reversed the decreased invasiveness of NaPa-treated cells. Therefore we can conclude that the strong inhibition of MDA-MB-231 invasiveness is not due to a decrease in proteases involved in cell migration (u-PA and MMP) but could be related both to the modification of cell structure and an increased expression of adhesion molecules such as u-PAR and LFA-1. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: sodium phenylacetate, invasiveness, breast cancer, adhesive molecules

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Selected References

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  1. Adam L., Crépin M., Isräel L. Tumor growth inhibition, apoptosis, and Bcl-2 down-regulation of MCF-7ras tumors by sodium phenylacetate and tamoxifen combination. Cancer Res. 1997 Mar 15;57(6):1023–1029. [PubMed] [Google Scholar]
  2. Adam L., Crépin M., Savin C., Israël L. Sodium phenylacetate induces growth inhibition and Bcl-2 down-regulation and apoptosis in MCF7ras cells in vitro and in nude mice. Cancer Res. 1995 Nov 15;55(22):5156–5160. [PubMed] [Google Scholar]
  3. Alonso D. F., Farina H. G., Arregui C., Aon M. A., Gomez D. E. Modulation of urokinase-type plasminogen activator and metalloproteinase activities in cultured mouse mammary-carcinoma cells: enhancement by paclitaxel and inhibition by nocodazole. Int J Cancer. 1999 Oct 8;83(2):242–246. doi: 10.1002/(sici)1097-0215(19991008)83:2<242::aid-ijc16>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  4. Bajou K., Noël A., Gerard R. D., Masson V., Brunner N., Holst-Hansen C., Skobe M., Fusenig N. E., Carmeliet P., Collen D. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med. 1998 Aug;4(8):923–928. doi: 10.1038/nm0898-923. [DOI] [PubMed] [Google Scholar]
  5. Bianchi E., Cohen R. L., Thor A. T., Todd R. F., 3rd, Mizukami I. F., Lawrence D. A., Ljung B. M., Shuman M. A., Smith H. S. The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res. 1994 Feb 15;54(4):861–866. [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  7. Edvardsen K., Chen W., Rucklidge G., Walsh F. S., Obrink B., Bock E. Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down-regulates secretion of matrix metalloproteinases. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11463–11467. doi: 10.1073/pnas.90.24.11463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hayashi H., Shimizu R., Fujii K., Itoh S., Yang D., Onozaki K. Resistance to IL-1 anti-proliferative effect, accompanied by characteristics of advanced melanoma, permits invasion of human melanoma cells in vitro, but not metastasis in the nude mouse. Int J Cancer. 1997 May 2;71(3):416–421. doi: 10.1002/(sici)1097-0215(19970502)71:3<416::aid-ijc19>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  9. Hazan R. B., Phillips G. R., Qiao R. F., Norton L., Aaronson S. A. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol. 2000 Feb 21;148(4):779–790. doi: 10.1083/jcb.148.4.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Holst-Hansen C., Johannessen B., Høyer-Hansen G., Rømer J., Ellis V., Brünner N. Urokinase-type plasminogen activation in three human breast cancer cell lines correlates with their in vitro invasiveness. Clin Exp Metastasis. 1996 May;14(3):297–307. doi: 10.1007/BF00053903. [DOI] [PubMed] [Google Scholar]
  11. Loridon-Rosa B., Vielh P., Cuadrado C., Burtin P. Comparative distribution of fibronectin and vitronectin in human breast and colon carcinomas. An immunofluorescence study. Am J Clin Pathol. 1988 Jul;90(1):7–16. doi: 10.1093/ajcp/90.1.7. [DOI] [PubMed] [Google Scholar]
  12. Ogawa Y., Hirakawa K., Nakata B., Fujihara T., Sawada T., Kato Y., Yoshikawa K., Sowa M. Expression of intercellular adhesion molecule-1 in invasive breast cancer reflects low growth potential, negative lymph node involvement, and good prognosis. Clin Cancer Res. 1998 Jan;4(1):31–36. [PubMed] [Google Scholar]
  13. Ossowski L. Invasion of connective tissue by human carcinoma cell lines: requirement for urokinase, urokinase receptor, and interstitial collagenase. Cancer Res. 1992 Dec 15;52(24):6754–6760. [PubMed] [Google Scholar]
  14. Paysant J., Vasse M., Soria J., Lenormand B., Pourtau J., Vannier J. P., Soria C. Regulation of the uPAR/uPA system expressed on monocytes by the deactivating cytokines, IL-4, IL-10 and IL-13: consequences on cell adhesion to vitronectin and fibrinogen. Br J Haematol. 1998 Jan;100(1):45–51. doi: 10.1046/j.1365-2141.1998.00528.x. [DOI] [PubMed] [Google Scholar]
  15. Prasanna P., Shack S., Wilson V. L., Samid D. Phenylacetate in chemoprevention: in vitro and in vivo suppression of 5-aza-2'-deoxycytidine-induced carcinogenesis. Clin Cancer Res. 1995 Aug;1(8):865–871. [PubMed] [Google Scholar]
  16. Samid D., Shack S., Sherman L. T. Phenylacetate: a novel nontoxic inducer of tumor cell differentiation. Cancer Res. 1992 Apr 1;52(7):1988–1992. [PubMed] [Google Scholar]
  17. Samid D., Yeh A., Prasanna P. Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood. 1992 Sep 15;80(6):1576–1581. [PubMed] [Google Scholar]
  18. Schmitt M., Harbeck N., Thomssen C., Wilhelm O., Magdolen V., Reuning U., Ulm K., Höfler H., Jänicke F., Graeff H. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost. 1997 Jul;78(1):285–296. [PubMed] [Google Scholar]
  19. Suzuki N., Urano J., Tamanoi F. Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15356–15361. doi: 10.1073/pnas.95.26.15356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tatsumi T., Shimazaki C., Goto H., Araki S., Sudo Y., Yamagata N., Ashihara E., Inaba T., Fujita N., Nakagawa M. Expression of adhesion molecules on myeloma cells. Jpn J Cancer Res. 1996 Aug;87(8):837–842. doi: 10.1111/j.1349-7006.1996.tb02108.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Thibout D., Di Benedetto M., Kraemer M., Sainte-Catherine O., Derbin C., Crépin M. Sodium phenylacetate modulates the synthesis of autocrine and paracrine growth factors secreted by breast cancer cell lines. Anticancer Res. 1998 Jul-Aug;18(4A):2657–2661. [PubMed] [Google Scholar]
  22. Thibout D., Kraemer M., Di Benedetto M., Saffar L., Gattegno L., Derbin C., Crépin M. Sodium phenylacetate (NaPa) induces modifications of the proliferation, the adhesion and the cell cycle of tumoral epithelial breast cells. Anticancer Res. 1999 May-Jun;19(3A):2121–2126. [PubMed] [Google Scholar]

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