Abstract
The results of several epidemiological studies have suggested that a soybean-based diet is associated with a lower risk of prostate cancer. We investigated the effect of the soy isoflavone genistein on the proliferation and contact-stimulated migration of rat prostatic carcinoma MAT-LyLu and AT-2 cell lines. Genistein almost completely inhibited the growth of both MAT-LyLu and AT-2 cells in the concentration range from 25 to 100 μM, but the addition of 1 μM genistein to the medium significantly stimulated the proliferation of both cell lines. Additionally, at concentrations above 25 μM, genistein showed a potent cytotoxic effect. However, the central finding of this study is that at physiologically relevant concentrations (1 μM and 10 μM), genistein inhibits the motility of prostate cancer cells stimulated by homo-and heterotypic contacts. These results show that at physiological concentrations, genistein exerts an inhibitory effect on the migration of prostate cancer cells and suggest that it may be one of the factors responsible for the anti-metastatic activity of plant isoflavonoids
Key words: Cell movement, Metastasis, Contact-stimulation, Prostate cancer, Genistein
Full Text
The Full Text of this article is available as a PDF (720.0 KB).
Abbreviations used
- CME
coefficient of movement efficiency
- DiI
1,1′-dioctadecyl-3,3,3′,3′-tetrametylindocarbo-cyanine perchlorate
- FCS
fetal calf serum
References
- 1.Messina M.J., Persky V., Setchell K.D., Barnes S. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr. Cancer. 1994;21:113–131. doi: 10.1080/01635589409514310. [DOI] [PubMed] [Google Scholar]
- 2.Pollard M., Luckert P.H. Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats. Nutr. Cancer. 1997;28:41–45. doi: 10.1080/01635589709514551. [DOI] [PubMed] [Google Scholar]
- 3.Shen J.C., Klein R.D., Wei Q., Guan Y., Contois J.H., Wang T.T., Chang S., Hursting S.D. Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells. Mol. Carcinog. 2000;29:92–102. doi: 10.1002/1098-2744(200010)29:2<92::AID-MC6>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
- 4.Severson R.K., Nomura A.M., Grove J.S., Stemmermann G.N. A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res. 1989;49:1857–1860. [PubMed] [Google Scholar]
- 5.Schleicher R.L., Lamartiniere C.A., Zheng M., Zhang M. The inhibitory effect of genistein on the growth and metastasis of a transplantable rat accessory sex gland carcinoma. Cancer Lett. 1999;136:195–201. doi: 10.1016/S0304-3835(98)00322-X. [DOI] [PubMed] [Google Scholar]
- 6.Liu Y., Kyle E., Lieberman R., Crowell J., Kellof G., Bergan R.C. Focal adhesion kinase (FAK) phosphorylation is not required for genisteininduced FAK-beta-1-integrin complex formation. Clin. Exp. Metastasis. 2000;18:203–212. doi: 10.1023/A:1006729106034. [DOI] [PubMed] [Google Scholar]
- 7.Valachovicova T., Slivova V., Bergman H., Shuherk J., Sliva D. Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of NF-kappaB/AP-1-dependent and-independent pathways. Int. J. Oncol. 2004;25:1389–1395. [PubMed] [Google Scholar]
- 8.Iishi H., Tatsuta M., Baba M., Yano H., Sakai N., Akedo H. Genistein attenuates peritoneal metastasis of azoxymethane-induced intestinal adenocarcinomas in Wistar rats. Int. J. Cancer. 2000;86:416–420. doi: 10.1002/(SICI)1097-0215(20000501)86:3<416::AID-IJC17>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
- 9.Chambers A.F. The metastatic process: basic research and clinical implications. Oncology Res. 1999;11:161–168. [PubMed] [Google Scholar]
- 10.Grimstad I.A. Direct evidence that cancer cell locomotion contributes importantly to invasion. Exp. Cell. Res. 1987;173:515–523. doi: 10.1016/0014-4827(87)90291-6. [DOI] [PubMed] [Google Scholar]
- 11.Stracke M.L., Aznavoorian S.A., Beckner M.E., Liotta L.A., Schiffmann E. Cell motility, a principal requirement for metastasis. In: Goldberg I.D., editor. Cell Motility Factors. Basel: Birkhauser Verlag; 1991. pp. 147–162. [DOI] [PubMed] [Google Scholar]
- 12.Aznavoorian S., Stracke M.L., Krutzsch H., Schiffmann E., Liotta L.A. Signal transduction for chemotaxis and haptotaxis by matrix molecules in tumor cells. J. Cell Biol. 1990;110:1427–1438. doi: 10.1083/jcb.110.4.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Korohoda W., Madeja Z. Contact of sarcoma cells with aligned fibroblasts accelerates their displacement: computer-assisted analysis of tumour cell locomotion in co-culture. Biochem. Cell Biol. 1997;75:263–276. doi: 10.1139/bcb-75-3-263. [DOI] [PubMed] [Google Scholar]
- 14.Djamgoz M.B.A., Mycielska M., Madeja Z., Fraser S.P., Korohoda W. Directional movement of rat prostate cancer cells in electric field: Control by voltage-gated Na+ channel activity. J. Cell Sci. 2000;114:12697–12705. doi: 10.1242/jcs.114.14.2697. [DOI] [PubMed] [Google Scholar]
- 15.Madeja Z., Miękus K., Sroka J., Djamgoz M.B.A., Korohoda W. Homotypic cell-cell contacts stimulate the motile activity of rat prostate cancer cells. Br. J. Urol. Int. 2001;88:776–786. doi: 10.1046/j.1464-410x.2001.02349.x. [DOI] [PubMed] [Google Scholar]
- 16.Madeja Z., Szymkiewicz I., Żaczek A., Sroka J., Miękus K., Korohoda W. Contact-activated migration of melanoma B16 and sarcoma XC cells. Biochem. Cell Biol. 2001;79:425–440. doi: 10.1139/bcb-79-4-425. [DOI] [PubMed] [Google Scholar]
- 17.Miekus K., Czernik M., Sroka J., Czyz J., Madeja Z. Contact stimulation of prostate cancer cell migration: the role of gap junctional coupling and migration stimulated by heterotypic cell-to-cell contacts in determination of the metastatic phenotype of Dunning rat prostate cancer cells. Biol. Cell. 2005;97:893–903. doi: 10.1042/BC20040129. [DOI] [PubMed] [Google Scholar]
- 18.Madeja Z., Sroka J. Contact guidance of Walker carcinosarcoma cells by the underlying normal fibroblasts is inhibited by RGD-containing synthetic peptides. Folia Histochem. Cytobiol. 2002;40:251–260. [PubMed] [Google Scholar]
- 19.Madeja Z., Sroka J., Nystrom C., Bjorkhem-Bergman L., Nordman T., Damdimopoulos A., Nalvarte I., Eriksson L.C., Spyrou G., Olsson J.M., Bjornstedt M. The role of thioredoxin reductase activity in selenium-induced cytotoxicity. Biochem. Pharmacol. 2005;69:1765–1772. doi: 10.1016/j.bcp.2005.02.023. [DOI] [PubMed] [Google Scholar]
- 20.Sroka J., Kaminski R., Michalik M., Madeja Z., Przestalski S., Korohoda W. The effect of triethyllead on the motile activity of Walker 256 carcinosarcoma cells. Cell. Mol. Biol. Lett. 2004;9:15–30. [PubMed] [Google Scholar]
- 21.Hempstock J., Kavanagh J.P., George N.J. Growth inhibition of prostate cell lines in vitro by phyto-oestrogens. Br. J. Urol. 1998;82:560–563. doi: 10.1046/j.1464-410x.1998.00769.x. [DOI] [PubMed] [Google Scholar]
- 22.Lin X., Switzer B.R., Demark-Wahnefried W. Effect of mammalian lignans on the growth of prostate cancer cell lines. Anticancer Res. 2001;21:3995–3999. [PubMed] [Google Scholar]
- 23.Bhatia N., Agarwal R. Detrimental effect of cancer preventive phytochemicals silymarin, genistein and epigallocatechin 3-gallate on epigenetic events in human prostate carcinoma DU145 cells. Prostate. 2001;46:98–107. doi: 10.1002/1097-0045(20010201)46:2<98::AID-PROS1013>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
- 24.Papazisis K.T., Kalemi T.G., Zambouli D., Geromichalos G.D., Lambropoulos A.F., Kotsis A., Boutis L.L., Kortsaris A.H. Synergistic effects of protein tyrosine kinase inhibitor genistein with camptothecins against three cell lines in vitro. Cancer Lett. 2006;233:255–264. doi: 10.1016/j.canlet.2005.03.022. [DOI] [PubMed] [Google Scholar]
- 25.Pan W., Ikeda K., Takebe M., Yamori Y. Genistein, daidzein and glycitein inhibit growth and DNA synthesis of aortic smooth muscle cells from stroke-prone spontaneously hypertensive rats. J. Nutr. 2001;131:1154–1158. doi: 10.1093/jn/131.4.1154. [DOI] [PubMed] [Google Scholar]
- 26.Rickard D.J., Monroe D.G., Ruesink T.J., Khosla S., Riggs B.L., Spelsberg T.C. Phytoestrogen genistein acts as an estrogen agonist on human osteoblastic cells through estrogen receptors alpha and beta. J. Cell Biochem. 2003;89:633–646. doi: 10.1002/jcb.10539. [DOI] [PubMed] [Google Scholar]
- 27.Kumi-Diaka J., Saddler-Shawnette S., Aller A., Brown J. Potential mechanism of phytochemical-induced apoptosis in human prostate adenocarcinoma cells: Therapeutic synergy in genistein and β-lapachone combination treatment. Cancer Cell Int. 2004;5:1–9. doi: 10.1016/S1535-6108(03)00340-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.de Lemos M.L. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann. Pharmacother. 2001;35:1118–1121. doi: 10.1345/aph.10257. [DOI] [PubMed] [Google Scholar]
- 29.Wietrzyk J., Opolski A., Madej J., Radzikowski C. Antitumour and antimetastatic effect of genistein alone or combined with cyclophosphamide in mice transplanted with various tumours depends on the route of tumour transplantation. In Vivo. 2000;14:357–362. [PubMed] [Google Scholar]
- 30.Magee P.J., McGlynn H., Rowland I.R. Differential effects of isoflavones and lignans on invasiveness of MDA-MB-231 breast cancer cells in vitro. Cancer Lett. 2004;208:35–41. doi: 10.1016/j.canlet.2003.11.012. [DOI] [PubMed] [Google Scholar]
- 31.Alhasan S.A., Aranha O., Sarkar F.H. Genistein elicits pleiotropic molecular effects on head and neck cancer cells. Clin. Cancer Res. 2001;7:4174–4181. [PubMed] [Google Scholar]
- 32.Fotsis T., Pepper M., Adlercreutz H., Fleischmann G., Hase T., Montesano R., Schweigerer L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc. Natl. Acad. Sci. USA. 1993;90:2690–2694. doi: 10.1073/pnas.90.7.2690. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Wietrzyk J., Boratynski J., Grynkiewicz G., Ryczynski A., Radzikowski C., Opolski A. Antiangiogenic and antitumour effects in vivo of genistein applied alone or combined with cyclophosphamide. Anticancer Res. 2001;21:3893–3896. [PubMed] [Google Scholar]
- 34.Li Y., Sarkar F.H. Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3 prostate cancer cells treated with genistein. Cancer Lett. 2002;186:157–164. doi: 10.1016/S0304-3835(02)00349-X. [DOI] [PubMed] [Google Scholar]
- 35.Czyz J., Madeja Z., Irmer U., Korohoda W., Hulser D.F. Flavonoid apigenin inhibits motility and invasiveness of carcinoma cells in vitro. Int. J. Cancer. 2005;114(1):12–18. doi: 10.1002/ijc.20620. [DOI] [PubMed] [Google Scholar]
- 36.Abercrombie M. Contact inhibition and malignancy. Nature. 1979;281:259–262. doi: 10.1038/281259a0. [DOI] [PubMed] [Google Scholar]
- 37.Adlercreutz H., Markkanen H., Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet. 1993;342:1209–1210. doi: 10.1016/0140-6736(93)92188-Y. [DOI] [PubMed] [Google Scholar]
- 38.Morton M.S., Matos-Ferreira A., Abranches-Monteiro L., Correia R., Blacklock N., Chan P.S., Cheng C., Lloyd S., Chieh-ping W., Griffiths K. Measurement and metabolism of isoflavonoids and lignans in the human male. Cancer Lett. 1997;114:145–151. doi: 10.1016/S0304-3835(97)04646-6. [DOI] [PubMed] [Google Scholar]
- 39.Simoncini T., Scorticati C., Mannella P., Fadiel A., Giretti M.S., Fu X.D., Baldacci C., Garibaldi S., Caruso A., Fornari L., Naftolin F., Genazzani A.R. Estrogen receptor alpha interacts with Galpha13 to drive actin remodeling and endothelial cell migration via the RhoA/Rho kinase/moesin pathway. Mol. Endocrinol. 2006;20:1756–1771. doi: 10.1210/me.2005-0259. [DOI] [PubMed] [Google Scholar]