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The Pharmaceutical Society of Korea (대한약학회)
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Induction of Apoptotic Cell Death by a Ceramide Analog in PC-3 Prostate Cancer Cells

  • Oh, Ji-Eun (College of Pharmacy, Chung-Ang University) ;
  • So, Kwang-Sup (College of Pharmacy, Chung-Ang University) ;
  • Lim, Se-Jin (College of Pharmacy, Dong-Duk Women's University) ;
  • Kim, Mie-Young (College of Pharmacy, Chung-Ang University)
  • Published : 2006.12.31
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Abstract

Ceramide analogs are potential chemotherapeutic agents. We report that a ceramide analog induces apoptosis in human prostate cancer cells. The ceramide analog induced cell death through an apoptotic mechanism, which was demonstrated by DNA fragmentation, the cleavage of poly ADP ribose polymerase (PARP), and a loss of membrane asymmetry. Treating the cells with ceramide analog resulted in the release of various proapoptotic mitochondrial proteins including cytochrome c and Smac/DIBLO into the cytosol, and a decrease in the mitochondrial membrane potential. In addition, the ceramide analog decreased the phospho-Akt and phospho-Bad levels. The expression of the antiapoptotic Bcl-2 decreased slightly with increasing Bax to Bcl-2 ratio. These results suggest that the ceramide analog induces apoptosis by regulating multiple signaling pathways that involve the mitochondrial pathway.

Keywords

References

  1. Bieberich, E., Kawaguchi, T., and Yu, R. K., N-acylated serinol is a novel cermide mimic inducing apoptosis in neuroblastoma cells. J. Biol. Chem., 275, 177-181 (2000) https://doi.org/10.1074/jbc.275.1.177
  2. Cabot, M., Giuliano, A., Han, T. -Y., and Liu, Y. -Y., SDZ PSC 833, the cyclosporine A analogue and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitivity and drug-resistance cancer cells. Cancer Res., 59, 889-885 (1999)
  3. DiPaola, R. S. and Aisner, J., Overcoming bcl-2 and p53 mediated resistance in prostate cancer. Semin. Oncol., 26, 112-116 (1999)
  4. Finucane, D. M., Wetzel, E. B., Waterhouse, N. J., Cotter, T. G., and Green, D. R., Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J. Biol. Chem., 274, 2225-2233 (1999) https://doi.org/10.1074/jbc.274.4.2225
  5. Green, D. R. and Reed, J. C., Mitochondria and apoptosis. Science, 281, 1309-1312 (1998) https://doi.org/10.1126/science.281.5381.1309
  6. Gross, A., McDonnell, J. M., and Korsmeyer, S. J., Bcl-2 family members and the mitochondria in apoptosis. Genes & Dev., 13, 1899-1911 (1999) https://doi.org/10.1101/gad.13.15.1899
  7. Hannun, Y. A., Functions of ceramide in coordinating cellular responses to stress. Science, 274, 1855-1859 (1996) https://doi.org/10.1126/science.274.5294.1855
  8. Hannun, Y. A. and Obeid, L. M., The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J. Biol. Chem., 277, 25847-25850 (2002) https://doi.org/10.1074/jbc.R200008200
  9. Herr, I., Wilhelm, D., Bohler, T., Angel, P., and Debatin, K., Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J., 16, 6200-6208 (1997) https://doi.org/10.1093/emboj/16.20.6200
  10. Jaffrezou, J-P., Levade, T., Bettaieb, A., Andrieu, N., Bezombes, C., Maestre, N., Vermeersch, S., Rousse, A., and Lauren,t B., Daunorubicin induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J., 15, 2417-2424 (1996)
  11. Kaufmann, S. H., Desnoyers, S., Ottaviano, Y., Davidson, N. E., and Poirier, G. G., Specific proteolytic cleavage of poly (ADPribose) polymerase: an early marker of chemotherapyinduced apoptosis. Cancer Res., 53, 3976-3985 (1993)
  12. Kennedy, S. G., Kandel, E. S., Cross, T. K., and Hay, N., Akt/ protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol. Cell. Biol., 19, 5800- 5810 (1999) https://doi.org/10.1128/MCB.19.8.5800
  13. Kim, H. J., Mun, J. Y., Chun, Y. J., Choi, K. H., and Kim, M. Y., Bax-dependent apoptosis induced by ceramide in HL-60 cells. FEBS Lett., 505, 264-268 (2001) https://doi.org/10.1016/S0014-5793(01)02836-8
  14. Kim, H. J., Kang, S. K., Mun, J. Y., Chun, Y. J., Choi, K. H., and Kim, M. Y., Involvement of Akt in mitochndria-dependent apoptosis induced by a cdc25 phosphatase inhibitor naphthoquinone analog. FEBS Lett., 555, 217-222 (2003) https://doi.org/10.1016/S0014-5793(03)01238-9
  15. Kuwana, T. and Newmeyer, D. D., Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr. Opin. Cell Biol., 15, 691-699 (2003) https://doi.org/10.1016/j.ceb.2003.10.004
  16. Li, H., Zhu, H., Xu, C. J., and Yuan, J., Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell, 94, 491-501 (1998) https://doi.org/10.1016/S0092-8674(00)81590-1
  17. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X., Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell, 86, 147-157 (1996) https://doi.org/10.1016/S0092-8674(00)80085-9
  18. Macchia, M., Barontini, S., Bertini, S., Bussolo, V. D., Fogli, S., Giovannetti, E., Grossi, E., Minutolo, F., and Danesi, R., Design, Synthesis, and Characterization of the antitumor activity of novel ceramide analogues. J. Med. Chem., 44, 3998-4000 (2001)
  19. Obeid, L. M., Linardic, C. M., Karolak, L. A., and Hannun, Y. A., Programmed cell death by ceramide. Science, 259, 1769- 1771 (1993) https://doi.org/10.1126/science.8456305
  20. Osaki, M., Oshimura, M., and Ito, H., PI3K-Akt pathway; its functions and alterations in human cancer. Apoptosis, 9, 667- 676 (2004) https://doi.org/10.1023/B:APPT.0000045801.15585.dd
  21. Van Duijn, P. W. and Trapman, J., PI3K/Akt signaling regulates p27kip1 expression via Skp2 in PC3 and DU145 prostate cancer cells, but is not a major factor in p27kip1 regulation in LNCaP and PC346 cells. The Prostate, 66, 749-760, (2006) https://doi.org/10.1002/pros.20398
  22. Selzner, M., Bielawska, A., Morse, M. A., Rudiger, H. A., Sindram, D., Hannun, Y. A., and Clavien, P., Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res., 61, 1233-1240 (2001)
  23. Senchenkov, A., Litvak, D. A., and Cabot, M. C., Targeting ceramide metabolism- a strategy for overcoming drug resistance. J. Natl. Cancer Inst., 93, 347-357 (2001) https://doi.org/10.1093/jnci/93.5.347
  24. Struckhoff, A. P., Bittman, R., Burow, M. E., Clejan, S., Elliott, S., Hammond, T., Tang, Y., and Beckman, S., Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J. Pharmacol. Exp. Ther., 309, 523-532 (2004) https://doi.org/10.1124/jpet.103.062760
  25. Testa, J. R. and Bellacosa, A., Akt plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. U.S.A., 98, 10983-10985 (2001)
  26. Wang, C. Y., Cusack, J. C., Liu, R., and Baldwin, A. S., Control of inducible chemoresistance enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-$_ΚB$. Nat. Med., 5, 412-427 (1999) https://doi.org/10.1038/7410
  27. Zhang, L., Yu, J., Park, B. H., Kinzler, K. W., and Vogelstein, B., Role of BAX in the apoptotic response to anticancer agents. Science, 290, 989-992 (2000) https://doi.org/10.1126/science.290.5493.989
  28. Zhou, H., Li, X. M., Meinkoth, J., and Pittman, R. N., Akt regulates cell survival and apoptosis at a postmitochondrial level. J. Cell Biol., 151, 483-494 (2000) https://doi.org/10.1083/jcb.151.3.483