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Apigenin inhibits growth and motility but increases gap junctional coupling intensity in rat prostate carcinoma (MAT-LyLu) cell populations

Abstract

Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid abundant in the common fruits, herbs and vegetables constituting the bulk of the human diet. This study was aimed at quantifying the effects of apigenin on the basic cellular traits determining cancer development, i.e. cell proliferation, gap junctional coupling, and motility, using the Dunning rat prostate MAT-LyLu cell model. We demonstrated that apigenin considerably inhibits MAT-LyLu cell proliferation and significantly enhances the intensity of connexin43-mediated gap junctional coupling. This effect correlates with an increased abundance of C×43-positive plaques at the cell-to-cell borders seen in apigenin-treated variants. Moreover, we observed an inhibitory effect of apigenin on the motility of MAT-LyLu cells. The basic parameters characterising MAT-LyLu cell motility, especially the rate of cell displacement, considerably decreased upon apigenin administration. This in vitro data indicates that apigenin may affect cancer development in general, and prostate carcinogenesis in particular, via its influence on cellular activities decisive for both cancer promotion and progression, including cell proliferation, gap junctional coupling and cell motility and invasiveness.

Abbreviations

C×43:

connexin43

References

  1. Yamasaki, H., Krutovskikh, V., Mesnil, M., Tanaka, T., Zaidan-Dagli, M.L. and Omori, Y. Role of connexin (gap junction) genes in cell growth control and carcinogenesis. C. R. Acad. Sci. III 322 (1999) 151–159.

    PubMed  CAS  Google Scholar 

  2. Zhang, Y.W., Kaneda, M. and Morita, I. The gap junction-independent tumor-suppressing effect of connexin 43. J. Biol. Chem. 278 (2003) 44852–44856.

    PubMed  Article  CAS  Google Scholar 

  3. Guo, W. and Giancotti, F.G. Integrin signalling during tumour progression. Nat. Rev. Mol. Cell Biol. 5 (2004) 816–826.

    PubMed  Article  CAS  Google Scholar 

  4. Gupta, G.P. and Massague, J. Cancer metastasis: building a framework. Cell 127 (2006) 679–695.

    PubMed  Article  CAS  Google Scholar 

  5. Yamaguchi, H., Wyckoff, J. and Condeelis, J. Cell migration in tumors. Curr. Opin. Cell Biol. 17 (2005) 559–564.

    PubMed  Article  CAS  Google Scholar 

  6. Chambers, A.F. The metastatic process: basic research and clinical implications. Oncol. Res. 11 (1999) 161–168.

    PubMed  CAS  Google Scholar 

  7. Czyż, J. Stage-Specific Function of gap junctions during tumorigenesis. Cell. Mol. Biol. Lett. 13 (2008) 92–102.

    PubMed  Article  CAS  Google Scholar 

  8. Lambert, J.D., Hong, J., Yang, G.Y., Liao, J. and Yang, C.S. Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations. Am. J. Clin. Nutr. 81 (2005) 284S–291S.

    PubMed  CAS  Google Scholar 

  9. Sarkar, F.H. and Li, Y. The role of isoflavones in cancer chemoprevention. Front Biosci. 9 (2004) 2714–2724.

    PubMed  Article  CAS  Google Scholar 

  10. Patel, D., Shukla, S. and Gupta, S. Apigenin and cancer chemoprevention: progress, potential and promise (review). Int. J. Oncol. 30 (2007) 233–245.

    PubMed  CAS  Google Scholar 

  11. Birt, D.F., Mitchell, D., Gold, B., Pour, P. and Pinch, H.C. Inhibition of ultraviolet light induced skin carcinogenesis in SKH-1 mice by apigenin, a plant flavonoid. Anticancer Res. 17 (1997) 85–91.

    PubMed  CAS  Google Scholar 

  12. Lepley, D.M., Li, B., Birt, D.F. and Pelling, J.C. The chemopreventive flavonoid apigenin induces G2/M arrest in keratinocytes. Carcinogenesis 17 (1996) 2367–2375.

    PubMed  Article  CAS  Google Scholar 

  13. Lepley, D.M. and Pelling, J.C. Induction of p21/WAF1 and G1 cell-cycle arrest by the chemopreventive agent apigenin. Mol. Carcinog. 19 (1997) 74–82.

    PubMed  Article  CAS  Google Scholar 

  14. Gupta, S., Afaq, F. and Mukhtar, H. Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem. Biophys. Res. Commun. 287 (2001) 914–920.

    PubMed  Article  CAS  Google Scholar 

  15. Shukla, S., Mishra, A., Fu, P., MacLennan, G.T., Resnick, M.I. and Gupta, S. Up-regulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. FASEB J. 19 (2005) 2042–2044.

    PubMed  CAS  Google Scholar 

  16. Ujiki, M.B., Ding, X.Z., Salabat, M.R., Bentrem, D.J., Golkar, L., Milam, B., Talamonti, M.S., Bell, R.H., Jr., Iwamura, T. and Adrian, T.E. Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest. Mol. Cancer 5 (2006) 76.

    PubMed  Article  CAS  Google Scholar 

  17. Shukla, S. and Gupta, S. Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell Cycle 6 (2007) 1102–1114.

    PubMed  CAS  Google Scholar 

  18. Caltagirone, S., Rossi, C., Poggi, A., Ranelletti, F.O., Natali, P.G., Brunetti, M., Aiello, F.B. and Piantelli, M. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int. J. Cancer 87 (2000) 595–600.

    PubMed  Article  CAS  Google Scholar 

  19. Czyż, J., Madeja, Z., Irmer, U., Korohoda, W. and Hulser, D.F. Flavonoid apigenin inhibits motility and invasiveness of carcinoma cells in vitro. Int. J. Cancer 114 (2005) 12–18.

    PubMed  Article  CAS  Google Scholar 

  20. Piantelli, M., Rossi, C., Iezzi, M., La Sorda, R., Iacobelli, S., Alberti, S. and Natali, P.G. Flavonoids inhibit melanoma lung metastasis by impairing tumor cells endothelium interactions. J. Cell. Physiol. 207 (2006) 23–29.

    PubMed  Article  CAS  Google Scholar 

  21. Gopalakrishnan, A., Xu, C.J., Nair, S.S., Chen, C., Hebbar, V. and Kong, A.N. Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells. Arch. Pharm. Res. 29 (2006) 633–644.

    PubMed  CAS  Article  Google Scholar 

  22. Madeja, Z., Miekus, K., Sroka, J., Djamgoz, M.B. and Korohoda, W. Homotypic cell-cell contacts stimulate the motile activity of rat prostate cancer cells. BJU Int. 88 (2001) 776–786.

    PubMed  Article  CAS  Google Scholar 

  23. Miêkus, K. and Madeja, Z. Genistein inhibits the contact-stimulated migration of prostate cancer cells. Cell. Mol. Biol. Lett. 12 (2007) 348–361.

    Article  CAS  Google Scholar 

  24. Chaumontet, C., Bex, V., Gaillard-Sanchez, I., Seillan-Heberden, C., Suschetet, M. and Martel, P. Apigenin and tangeretin enhance gap junctional intercellular communication in rat liver epithelial cells. Carcinogenesis 15 (1994) 2325–2330.

    PubMed  Article  CAS  Google Scholar 

  25. Czyż, J., Irmer, U., Schulz, G., Mindermann, A. and Hulser, D.F. Gapjunctional coupling measured by flow cytometry. Exp. Cell Res. 255 (2000) 40–46.

    PubMed  Article  CAS  Google Scholar 

  26. Czyż, J., Guan, K., Zeng, Q. and Wobus, A.M. Loss of beta 1 integrin function results in upregulation of connexin expression in embryonic stem cell-derived cardiomyocytes. Int. J. Dev. Biol. 49 (2005) 33–41.

    PubMed  Article  CAS  Google Scholar 

  27. Sroka, J., Kamiñski, R., Michalik, M., Madeja, Z., Przestalski, S. and Korohoda, W. The effect of triethyllead on the motile activity of walker 256 carcinosarcoma cells. Cell. Mol. Biol. Lett. 9 (2004) 15–30.

    PubMed  CAS  Google Scholar 

  28. Czyż, J., Irmer, U., Zappe, C., Mauz, M. and Hulser, D.F. Hierarchy of carcinoma cell responses to apigenin: gap junctional coupling versus proliferation. Oncol. Rep. 11 (2004) 739–744.

    PubMed  Google Scholar 

  29. Wang, W., Heideman, L., Chung, C.S., Pelling, J. C., Koehler, K.J. and Birt, D.F. Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol. Carcinog. 28 (2000) 102–110.

    PubMed  Article  Google Scholar 

  30. Chaumontet, C., Droumaguet, C., Bex, V., Heberden, C., Gaillard-Sanchez, I. and Martel, P. Flavonoids (apigenin, tangeretin) counteract tumor promoter-induced inhibition of intercellular communication of rat liver epithelial cells. Cancer Lett. 114 (1997) 207–210.

    PubMed  Article  CAS  Google Scholar 

  31. Grimstad, I.A. Direct evidence that cancer cell locomotion contributes importantly to invasion. Exp. Cell Res. 173 (1987) 515–523.

    PubMed  Article  CAS  Google Scholar 

  32. Miêkus, K., Czernik, M., Sroka, J., Czyż, J. and 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 97 (2005) 893–903.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Jarosław Czyż.

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Paper authored by participants of the international conference: XXXIV Winter School of the Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Zakopane, March 7–11, 2007, “The Cell and Its Environment”. Publication cost was covered by the organisers of this meeting.

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Czernik, M., Sroka, J., Madeja, Z. et al. Apigenin inhibits growth and motility but increases gap junctional coupling intensity in rat prostate carcinoma (MAT-LyLu) cell populations. Cell Mol Biol Lett 13, 327–338 (2008). https://doi.org/10.2478/s11658-008-0003-z

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  • DOI: https://doi.org/10.2478/s11658-008-0003-z

Keywords

  • Prostate cancer
  • Cell motility
  • Gap junctional coupling
  • Apigenin