Melittin Inhibits Human Prostate Cancer Cell Growth through Induction of Apoptotic Cell Death

  • Park Hye-Ji (College of Pharmacy, Chungbuk National University) ;
  • Lee Yong-Kyung (College of Pharmacy, Chungbuk National University) ;
  • Song Ho-Seub (College of Oriental Medicin, Kyungwon University) ;
  • Kim Goon-Joung (College of Oriental Medicin, Kyungwon University) ;
  • Son Dong-Ju (College of Pharmacy, Chungbuk National University) ;
  • Lee Jae-Woong (College of Pharmacy, Chungbuk National University) ;
  • Hong Jin-Tae (College of Pharmacy, Chungbuk National University)
  • 발행 : 2006.03.01

초록

It was previously found that melittin inhibited $NF-{\kappa}B$ activity by reacting with signal molecules of $NF-{\kappa}B$ which is critical contributor in cancer cell growth by induction of apoptotic cell death. We here investigated whether melittin inhibits cell growth of human prostate cancer cells through induction of apoptotic cell death, and the possible signal pathways. Melittin ($0{\sim}1\;{\mu}g/ml$) inhibited prostate cancer cell growth in a dose dependent manner. Conversely related to the growth inhibitory effect, melittin increased the induction of apoptotic cell death in a dose dependent manner. Melittin also inhibited DNA binding activity of $NF-{\kappa}B$, an anti-apoptotic transcriptional factor. Consistent with the induction of apoptotic cell death and inhibition of $NF-{\kappa}B$, melittin increased the expression of pro-apoptotic proteins caspase-3, and Bax but down-regulated anti-apoptotic protein Bcl-2. These findings suggest that melittin could inhibit prostate cancer cell growth, and this effect may be related with the induction of apoptotic cell death via inactivation of $NF-{\kappa}B$.

키워드

참고문헌

  1. Aggarwal, B.B. (2004): Nuclear factor-kappaB: the enemy within. Cancer Cel., 6, 203-208 https://doi.org/10.1016/j.ccr.2004.09.003
  2. Adhami, V.M., Siddiqui, I.A., Ahmad, N., Gupta, S. and Mukhtar, H. (2004): Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. Cancer Res., 64, 8715-8722 https://doi.org/10.1158/0008-5472.CAN-04-2840
  3. Bosland, M.C., McCormick, D.L., Melamed, J., Walden, P.D., Jacquotte, A.Z. and Lumey, L.H. (2002): Chemoprevention strategy for prostate cancer. Eur. J. Cancer Chemoprev., 11, s18-s27
  4. Brown, R.L., Haley, T.L., West, K.A. and Crabb, J.W. (1999): Pseudechetoxin: a peptide blocker of cyclic nucleotidegated ion channels. Proc. Natl. Acad. Sci. U.S.A., 2, 754-759
  5. Bruckheimer, E.M. and Kyprianou, N. (2000): Apoptosis in prostate carcinogenesis. A growth regulator and a therapeutic target. Cell Tissue Res., 301,152-162
  6. Chen, Y.Q., Zhu, Z.A., Hao, Y.Q., Dai, K.R. and Zhang, C. (2004): Effect of melittin on apoptosis and necrosis of U2 OS cells. Zhong Xi Yi Jie He Xue Bao., 2, 208-209 https://doi.org/10.3736/jcim20040317
  7. Feldman, B.J. and Feldman, D. (2001): The development of androgen-independent prostate cancer. Nat. Rev. Cancer, 1, 34-45 https://doi.org/10.1038/35094009
  8. Gurumurthy, S., Vasudevan, K.M. and Rangnekar, V.M. (2001): Regulation of apoptosis in prostate cancer. Cancer Metastasis Rev., 20, 225-243 https://doi.org/10.1023/A:1015583310759
  9. Guseva, N.V., Taghiyev, A.F., Rokhlin, O.W. and Cohen, M.B. (2004): Death receptor-induced cell death in prostate cancer. J. Cell Biochem., 91, 70-99 https://doi.org/10.1002/jcb.10707
  10. Hider, R.C. (1998): Honeybee venom: a rich source of pharmacologically active peptides. Endeavour., 12, 60-65 https://doi.org/10.1016/0160-9327(88)90082-8
  11. Holle, L., Song, W., Holle, E., Wei, Y., Wagner, T. and Yu, X. (2003): A matrix metalloproteinase 2 cleavable melittin/ avidin conjugate specifically targets tumor cells in vitro and in vivo. Int. J. Oncol., 22, 93-98
  12. Jemal, A., Thomas, A., Murray, T. and Thun, M. (2003): Cancer statistics. CA Cancer J. Clin., 53, 5-26 https://doi.org/10.3322/canjclin.53.1.5
  13. Jentsch, J. and Mucke, H.W. (1997), Bee venom peptides XVIII. Peptide-m and mcd-peptide: Isolation and characterization. Int. J. Pept. Protein Res., 9, 78-79 https://doi.org/10.1111/j.1399-3011.1977.tb01840.x
  14. Kantoff, P.W. (1995): New agents in the therapy of hormonerefractory prostate cancer. Semin Oncol., 22, 32-34
  15. Kyprianou, N. and Isaacs, J.T. (1988): Activation of programmed cell death in the rat ventral prostate after castration. Endocrinology, 122, 552-562 https://doi.org/10.1210/endo-122-2-552
  16. Kyprianou, N., Tu, H. and Jacobs, S.C. (1996): Apoptotic versus proliferative activities in human benign prostatic hyperplasia. Hum. Pathol., 27, 668-672 https://doi.org/10.1016/S0046-8177(96)90396-2
  17. Leuschner, C., Enright, F.M., Gawronska, B. and Hansel, W. (2003): Membrane disrupting lytic peptide conjugates destroy hormone dependent and independent breast cancer cells in vitro and in vivo. Breast Cancer Res Treat., 78, 17-27 https://doi.org/10.1023/A:1022169525521
  18. Li, Y. and Sarkar, F.H. (2002): Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res., 8, 2369-2377
  19. Ling, C.Q., Li, B., Zhang, C., Zhu, D.Z., Huang, X.Q., Gu, W. and Li, S.X. (2005): Inhibitory effect of recombinant adenovirus carrying melittin gene on hepatocellular carcinoma. Ann Oncol., 16,109-115 https://doi.org/10.1093/annonc/mdi019
  20. Lowe, S.W. and Lin, A.W. (2000): Apoptosis in cancer. Carcinogenesis, 21, 485-495 https://doi.org/10.1093/carcin/21.3.485
  21. Park, H.J., Lee, S.H., Son, D.J., Oh, K.W., Kim, K.H., Song, H.S., Kim, G.J., Oh, G.T., Yoon, D.Y. and Hong, J.T. (2004): Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit. Arthritis Rheum., 50, 3504-3515 https://doi.org/10.1002/art.20626
  22. Pilat, M.J., Kamradt, J.M. and Pienta, K.J. (1998): Hormone resistance in prostate cancer. Cancer Metastasis, 17, 373-381 https://doi.org/10.1023/A:1006166511344
  23. Phoenix, D.A., Brandenburg, K. and Harris, F. (2001): An investigation into the membrane-interactive potential of the Escherichia coli KpsE C-terminus. Biochem. Biophys. Res. Commun., 285, 976-980 https://doi.org/10.1006/bbrc.2001.5266
  24. Price, J.H., Hillman, K.S., Toral, M.E. and Newell, S. (1983): The public's perceptions and misperceptions of arthritis. Arthritis Rheum., 26, 1023-1028 https://doi.org/10.1002/art.1780260812
  25. Samson, A., Scherf, T., Eisenstein, M., Chill, J. and Anglister, J. (2002): The mechanism for acetylcholine receptor inhibition by alpha-neurotoxins and species-specific resistance to alpha-bungarotoxin revealed by NMR. Neuron, 2, 319-332
  26. Sher, E., Giovannini, F., Boot, J. and Lang, B. (2000): Peptide neurotoxins, small-cell lung carcinoma andneurological paraneoplastic syndromes. Biochimie., 82, 927-936 https://doi.org/10.1016/S0300-9084(00)01165-2
  27. Son, D.J., Ha, S.J., Song, H.S., Lim, Y., Yun, Y.P., Moon, D.C., Park, Y.H., Park, B.S., Song, M.J. and Hong, J.T. (2006): Melittin inhibits vascular smooth muscle cell proliferation through induction of apoptosis via suppression of NF-{kappa}B and Akt activation and enhancement of apoptotic protein expression. J. Pharmacol. Exp. Ther., (in press)
  28. Suh, J., Payvandi, F., Edelstein, L.C., Amenta, P.S., Zong, W.X., Gelinas, C. and Rabson, A.B. (2002): Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate, 52, 183-200 https://doi.org/10.1002/pros.10082
  29. Suh, J. and Rabson, A.B. (2004): NF-kappaB activation in human prostate cancer: important mediator or epiphenomenon? J. Cell Biochem., 91, 100-117 https://doi.org/10.1002/jcb.10729
  30. Van, L.E. and Moyer, M. (1999): Peptide toxin blockers of voltage-sensitive K+ channels: inotropic effects on diaphragm. J. Appl. Physiol., 3, 1009-1016
  31. Wolf, B.B. and Green, D.R. (1999): Suicidal tendencies: apoptotic cell death by caspase family proteinases. J. Biol. Chem., 274, 20049-20052 https://doi.org/10.1074/jbc.274.29.20049