Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지

Cadmium Induces Cell Cycle Arrest and Change in Expression of Cell Cycle Related Proteins in Breast Cancer Cell Lines

  • Lee Young Joo (Endocrine Toxicology Division, National Institute of Toxicological Research, Department of Food and Nutrition, and Research Institute of Human Ecology, Seoul National University) ;
  • Kang Tae Seok (Endocrine Toxicology Division, National Institute of Toxicological Research) ;
  • Kim Tae Sung (Endocrine Toxicology Division, National Institute of Toxicological Research) ;
  • Moon Hyun Ju (Endocrine Toxicology Division, National Institute of Toxicological Research) ;
  • Kang Il Hyun (Endocrine Toxicology Division, National Institute of Toxicological Research) ;
  • Oh Ji Young (Endocrine Toxicology Division, National Institute of Toxicological Research) ;
  • Kwon Hoonjeong (Department of Food and Nutrition, and Research Institute of Human Ecology, Seoul National University) ;
  • Han Soon Young (Endocrine Toxicology Division, National Institute of Toxicological Research)
  • Published : 2005.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Cadmium is an environmental pollutant exposed from contaminated foods or cigarette smoking and known to cause oxidative damage in organs. We investigated the cadmium-induced apoptosis and cell arrest in human breast cancer cells, MCF-7 cells and MDA-MB-231 cells. Obvious apoptotic cell death was shown in CdCl₂ 100 μM treatment for 12 hr, which were determined by DAPI staining and flow cytometric analysis. In cell cycle analysis, MCF-7 cells and MDA-MB-231 cells were arrested in S phase and G2/M phase respectively. These could be explained by the induction of cell cycle inhibitory protein, p21/sup Waf1/Cip1/ and p27/sup Kip1/, expression and reduction of cyclin/Cdk complexes in both cell lines. The decreased expression of cyclin A and Cdk2 in MCF-7 cells and cyclin B1 and Cdc2 in MDA-MB-231 cells were consistent with the flow cytometric observation. p-ERK expression was increased dose-dependent manner in both cell lines. It suggests that ERK MAPK pathway are involved in cadmium-induced cell cycle arrest and apoptosis. Moreover, cotreatment of zinc (100 μM, 12 hr) recovered the cadmium-induced cell arrest in both cells, which shows cadmium-induced oxidative stress mediates apoptosis and cell cycle arrest in human breast cancer cells.

Keywords

References

  1. Chao, J.I. and Yang, J.L. (2001): Opposite roles of ERK and p38 Mitogen-Activated Protein Kinases in cadmiuminduced genotoxicity and mitotic arrest. Chem. Res. Toxicol., 14, 1193-1202 https://doi.org/10.1021/tx010041o
  2. Chuang, S.M., Wang, I.C. and Yang, J.L. (2000): Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. Carcinogenesis, 21, 1423-1432 https://doi.org/10.1093/carcin/21.7.1423
  3. Garcia-Morales, P., Saceda, M., Kenney, N., Kim, N., Salomon, D.S., Gottardis, M.M., Solomon, H.B., Sholler, P.F., Jordan, V.C. and Martin, M.B. (1994): Effect of cadmium on estrogen receptor levels and estrogen-induced responses human breast cancer cells. J. Biol. Chem., 269, 16896-16901
  4. Hsu, P.C., Liu, M.Y., Hsu, C.C., Chen, L.Y. and Guo, Y.L. (1998): Effects of vitamin E and/or C on reactive oxygen species-related lead toxicity in the rat sperm. Toxicology, 128, 169-179 https://doi.org/10.1016/S0300-483X(98)00068-7
  5. IARC (1993): Beryllium, cadmium, mercury and exposures in the glass manufacturing industry. In IARC Monographs on the Evaluation of Carcinogenic Risks to Human, 58, 41117, International Agency for Research on Cancer, Lyon
  6. Kim, M.S., Kim, B.J., Woo, H.N., Kim, K.W., Kim, K.B., Kim, I.K. and Jung, Y.K. (2000): Cadmium induces caspase-mediated cell death: suppression by Bcl-2. Toxicology, 145, 27-37 https://doi.org/10.1016/S0300-483X(99)00176-6
  7. Koizumi, S. and Yamada, H. (2003): DNA microarray analysis of altered gene expression in cadmium-exposed human cells. J. Occup. Health, 45, 331-334 https://doi.org/10.1539/joh.45.331
  8. Park, K.S., Ahn, Y., Kim, J.A., Yun, M.S., Seong, B.L. and Choi, K.Y. (2002): Extracellular zinc stimulates ERK-dependent activation of p21Cip/WAF1 and inhibits proliferation of colorectal cancer cells. Br. J. Pharmacol., 137, 597-607 https://doi.org/10.1038/sj.bjp.0704909
  9. Pietenpol, J.A. and Stewart, Z.A. (2002): Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology, 181-182, 475-481 https://doi.org/10.1016/S0300-483X(02)00460-2
  10. Sarkar, S., Yadav, P. and Bhatnagar, D. (1998): Lipid peroxidative damage on cadmium exposure and alterations in antioxidant system in rat erythrocytes: a study with relation to time. Biometals, 11, 153-157 https://doi.org/10.1023/A:1009286130324
  11. Son, M.H., Kang, K.W., Lee, C.H. and Kim, S.G. (2001): Potentiation of cadmium-induced cytotoxicity by sulfur amino acid deprivation through activation of exracellular signalregulated kinase 1/2 (ERK1/2) in conjunction with p38 kinase or c-jun N terminal kinase (JNK). Complete inhibition of the potentiated toxicity by U0126 and ERK1/2 and p38 kinase inhibitor. Biochem. Pharmacol., 62, 1379-1390 https://doi.org/10.1016/S0006-2952(01)00780-8
  12. Stohs, S.J. and Bagchi, D. (1995): Oxidative mechanisms in the toxicity of metal ions. Free Radic. Biol. Med., 18, 321-336 https://doi.org/10.1016/0891-5849(94)00159-H
  13. Szuster-Ciesielska, A., Stachura, A., Siotwinska, M., Kaminska, T., Sniezko, R., Paduch, R., Abramczyk, D., Filar, J. and Kandefer-Szerszen, M. (2000): The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive oxygen species (ROS) production in cell cultures. Toxicology, 145, 159-171 https://doi.org/10.1016/S0300-483X(00)00144-X
  14. Waalkes, M.P. and Diwan, B.A. (1999): Cadmium-induced inhibition of the growth and metastasis of human lung carcinoma xenografts: role of apoptosis. Carcinogenesis, 20, 65-70 https://doi.org/10.1093/carcin/20.1.65
  15. Waalkes, M.P. (2000): Cadmium carcinogenesis in review. J. Inorg. Biochem., 79, 241-4 https://doi.org/10.1016/S0162-0134(00)00009-X
  16. Warren, S., Patel, S. and Kapron, C.M. (2000): The effect of vitamin E exposure on cadmium toxicity in mouse embryo cells in vitro. Toxicology, 142, 119-126 https://doi.org/10.1016/S0300-483X(99)00132-8
  17. Yuan, C., Kadiiska, M., Achanzar, W.E., Mason, R.P. and Waalkes, M.P. (2000): Possible role of caspase-3 inhibition in cadmium-induced blockage of apoptosis. Toxicol. Appl. Pharmacol., 164, 321-329 https://doi.org/10.1006/taap.2000.8921
  18. Zimmermann, K.C., Bonzon, C. and Green, D.R. (2001): The machinery of programmed cell death. Pharmacol. Ther., 92, 57-70 https://doi.org/10.1016/S0163-7258(01)00159-0