Selenium arrest G1/S phase of cell cycle in LNCaP human prostate cancer cells

사람 전립선암세포주인 LNCaP에서 셀레늄의 G1/S 세포주기억제에 관한 연구

  • Nam, Jeong-Seok (Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science) ;
  • Jung, Ji-Youn (Department of Companion and Laboratory Animal Science, Kongju National University)
  • 남정석 (가천의과학대학교 이길여 암당뇨연구원) ;
  • 정지윤 (공주대학교 특수동물학과)
  • Published : 2009.09.30

Abstract

The trace element nutrient selenium discharges its well-known nutritional anti-tumor activity. Converging data from epidemiological, ecological and clinical studies have shown that selenium can decrease the risk for some types of human cancers, especially those of the prostate, lung, and colon. Mechanistic studies have indicated that selenium has many desirable attributes of chemoprevention targeting cancer cells through DNA single strand breaks, the induction of reactive oxygen species. However, there is no reports about the relationship between methylseleninic acid (MSeA), one of methylselenol metabolites and cell cycle arrest in LNCaP human prostate cancer cells. Our data showed that MSeA arrested G1/S pahse of cell cycle arrest and inhibited DNA synthesis in LNCaP cells and those cellular events by MSeA were due to the induction ofp27 protein which is a well-known cyclin-dependent kinase inhibitor. Taken together, cell cycle arrest occurred by MSeA may contribute to the growth-inhibition of prostate cancer cells.

우리 몸에 필수적인 미량원소인 셀레늄은 항암활성이 있는 것으로 알려져 있고, 역학적, 생태학적 그리고 임상시험을 종합해보면, 셀레늄은 종양, 특히 전립선암, 폐암, 대장암에 대한 위험성을 낮출 수 있을 것으로 생각되어진다. 기전연구에 따르면 셀레늄은 DNA single strand breaks와 활성산소종을 유도함으로써 종양을 억제하는 예방효능이 있는 것으로 밝혀지고 있다. 하지만, 아직까지 전립선암세포주에서 methylseloenol 대사체 중에 하나인 MSeA와 세포주기억제와의 관계에 대해서는 명확하게 밝혀져 있지 않은 실정이다. 따라서, 이번 연구에서는 전립선암세포주에서 셀레늄의 세포주기에 관한 효능을 확인해 보고자 하였다. 결과를 종합해보면, MSeA는 전립선암세포주에서 G1/S기 세포주기를 억제하고 DNA 합성을 방해하는 것으로 나타났고, 이러한 현상은 cyclin의존성 키나아제를 길항하는 단백질 중에 하나인 p27단백질의 발현을 증가시킴으로써 일어남을 확인하였다. 따라서, MSeA에 의해 유발되는 세포주기 억제가 전립선암 세포의 성장억제에 기여하는 것으로 사료된다.

Keywords

References

  1. 김원재, 정재일, 홍준혁, 김청수, 정세일, 윤덕기: 한국의 비뇨기 종양에 관한 역학 조사 (1998-2002). 대한비뇨기과학회지, 45, 1081-1088 (2004)
  2. Klein, E.A. and Thompson, I.M.: Update on chemoprevention of prostate cancer. Curr. Opin. Urol, 14, 143-149 (2004) https://doi.org/10.1097/00042307-200405000-00002
  3. 송승훈, 송강현, 이상복, 김청수: 한국인에서 혈중 셀레늄(Selenium) 농도의 연령별 변화와 전립선암과의 상관관계. 대한비뇨기과학회지. 47, 150-153 (2006) https://doi.org/10.4111/kju.2006.47.2.150
  4. Schwarz, K. and Foltz, C.M.: Selenium as an integral part of factor 3 against dietary necrotic liver degeneration-1951. Nutrition, 15,255 (1999)
  5. Rotruck, J.T., Pope, A.L., Ganther, H.E., Swanson, A.B., Hafeman, D.Gand Hoekstra, W.G: Selenium: biochemical role as a component of glutathione peroxidase. Science, 179, 588-590 (1973) https://doi.org/10.1126/science.179.4073.588
  6. El-Bayoumy, K.: The protective role of selenium on genetic damage and on cancer. Mutat. Res, 475, 123-139 (2001) https://doi.org/10.1016/S0027-5107(01)00075-6
  7. Gopalakrishna, R., Chen, Z.H. and Gundimeda, U.: Selenocompounds induce a redox modulation of protein kinase C in the cell, compartmentally independent from cytosolic glutathione: its role in inhibition of tumor promotion. Arch. Biochem. Biophys, 348,37-48 (1997) https://doi.org/10.1006/abbi.1997.0335
  8. Sinha, R., Kiley, S.C., Lu, J.X., Thompson, H.J., Moraes, R., Jaken, S. and Medina, D.: Effects of methylselenocysteine on PKC activity, cdk2 phosphorylation and gadd gene expression in synchronized mouse manunary epithelial tumor cells. Cancer Lett, 146, 135-145 (1999) https://doi.org/10.1016/S0304-3835(99)00250-5
  9. Clark, L.C., Combs, G.F. and Turnbull, B.W: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer trial. JAMA. 276. 1957-1963 (1996) https://doi.org/10.1001/jama.276.24.1957
  10. Wang, Z., Jiang, C. and Lu, J.: Induction of caspase-mediated apoptosis and cell cycle G1 arrest by selenium metabolite methylselenol. Mol. Carcinogenesis. 34. 113-120 (2002) https://doi.org/10.1002/mc.10056
  11. Jiang, C., Wang, Z., Ganther, H. and Lu, J.: Distinct Effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells. Mol. Cancer. Ther, 1. 1059-1066 (2002)
  12. Hu, H., Jiang, C., Ip, C., Rustum, Y.M. and Lu, J.: Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells. Clinical. Cancer. Res, 11.2379-2388 (2005) https://doi.org/10.1158/1078-0432.CCR-04-2084
  13. Hu, H., Jiang, C., Li, G and Lu, J.: PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. Carcinogenesis. 26. 1374-1381 (2005) https://doi.org/10.1093/carcin/bgi094
  14. Jiang, C., Hu, H., Malewicz, B., Wang, Z. and Lu, J.: Selenite- induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells. Mol. Cancer. Ther, 3. 877-884 (2005)
  15. Cho, S.D., Jiang, C., Malewicz, B., Dong, Y, Young, C., Kang, K.S., Lee, YS., Ip, C. and Lu, J.: Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgenstimulated transcription. Mol. Cancer. Ther, 3. 605-611 (2004)
  16. Yoon, S.O., Kim, M.M. and Chung, A.S.: Inhibitory effect of selenite on invasion of HT1080 tumor cells. J. BioI. Chem, 276,20085-20092 (2001) https://doi.org/10.1074/jbc.M101143200
  17. Wang, Z., Hu, Hm., Li, G, Lee, H.J., Jiang, C., Kim, S.H. and Lu, J.: Methylseleninic acid inhibits microvascular endothelial G1 cell cycle progression and decreases tumor microvessel density. Int. J. Cancer, 122, 15-24 (2008) https://doi.org/10.1002/ijc.23077
  18. Kaeck, M., Lu, J., Strange, R., Ip, C., Ganther, H. and Thompson, H.J.: Differential induction of growth arrest inducible genes by selenium compounds. Biochem. Pharmacal, 53, 921-926 (1997) https://doi.org/10.1016/S0006-2952(97)00103-2
  19. Sinha, R., Said, T.K. and Medina, D.: Organic and inorganic selenium compounds inhibit mouse mammary cell growth in vitro by different cellular pathways. Cancer Lett. 107. 277-284 (1996) https://doi.org/10.1016/0304-3835(96)04373-X
  20. Chung, A.S., Yoon, S.O., Jung, U. and Park, J.M.: Effect of Selenium on Chemoprevention and Metastasis. J. Kor. Cancer. Prevention, 8, 45-52 (2003)
  21. Sherr, C.J. and Roberts, J.M.: CDK inhibitors: positive and negative regulators of G1 phase progression. Genes. Dev, 13, 1501-1512 (1999) https://doi.org/10.1101/gad.13.12.1501
  22. Elledge, S. J. and Harper, J.w.: Cdk inhibitors: on the threshold of checkpoints and development. Curr. Opin. Cell BioI, 6, 847-852 (1994) https://doi.org/10.1016/0955-0674(94)90055-8
  23. Sherr, C. J.: The Pezcoller lecture: cancer cell cycles revisited. Cancer Res, 60, 3689-3695 (2000)
  24. Weinberg, R. A.: The retinoblastoma protein and cell cycle control. Cell, 81,323-330 (1995) https://doi.org/10.1016/0092-8674(95)90385-2
  25. Harper, J. W.: Cyclin dependent kinase inhibitors. Cencer Surv, 29,91-107 (1997)
  26. Xiong, Y., Hannon, G.J., Zhang, H., Casso, D., Kobayashi, R. and Beach, D.: p21 is a universal inhibitor of cyclin kinases. Nature, 366,701-704 (1993) https://doi.org/10.1038/366701a0