PD98059 Induces the Apoptosis of Human Cervical Cancer Cells by Regulating the Expression of Bcl2 and ERK2

  • Yang, Eun-Ju (Department of Clinical Laboratory Science, Daegu Haany University) ;
  • Chang, Jeong-Hyun (Department of Clinical Laboratory Science, Daegu Haany University)
  • Received : 2011.12.21
  • Accepted : 2011.12.31
  • Published : 2011.12.31

Abstract

PD98059 is the specific inhibitor of extracellular signaling-regulated kinase (ERK) kinase (MEK). ERK is involved in a mitogen-activated protein kinase (MAPK) cascade controlling cell growth and differentiation. Although the inhibition of ERK is known to induce cell death in various cell lines, this effect is still controversial and the role of PD98059 on the death of HeLa $S_3$ cells, a subclone of the cervical cancer cell line, is not well understood. The apoptosis of HeLa $S_3$ cells increased after the treatment of 50 ${\mu}M$ PD98059. The induction of apoptosis by PD98059 was occurred in a time- and a dose-dependent manners. The expression of Bcl-2 was reduced in accordance with decrease of ERK2 expression. Taken together, these results indicate that PD98059 has a cytotoxicity in HeLa $S_3$ cells and it may be used as a potential target for the treatment of cervical cancer.

Keywords

References

  1. Abraham R, Schäfer J, Rothe M, Bange J, Knyazev P, Ullrich A. Identification of MMP-15 as an anti-apoptotic factor in cancer cells. J Biol Chem. 2005. 280: 123-132.
  2. Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activagted protein kinase kinase in vitro and in vivo. J Biol Chem. 1995. 270: 27489-27494. https://doi.org/10.1074/jbc.270.46.27489
  3. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003. 3: 11-22. https://doi.org/10.1038/nrc969
  4. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA. 1995. 92: 7686-7689. https://doi.org/10.1073/pnas.92.17.7686
  5. Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, Connors RW, Bridges AJ. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science. 1994. 265: 1093-1095. https://doi.org/10.1126/science.8066447
  6. Gross A, McDonnell JM, Korsmeyer SJ. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 1999. 13: 1899-1911. https://doi.org/10.1101/gad.13.15.1899
  7. Hilger RA, Scheulen ME, Strumberg D. The Ras-Raf-MEK-ERK pathway in the treatment of cancer. Onkologie. 2002. 25: 511-518. https://doi.org/10.1159/000068621
  8. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 1999. 18: 813-822. https://doi.org/10.1038/sj.onc.1202367
  9. Kim SH, Kim SH, Kim YB, Jeon YT, Lee SC, Song YS. Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells. Ann N Y Acad Sci. 2009. 1171: 495-500. https://doi.org/10.1111/j.1749-6632.2009.04899.x
  10. Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995. 80: 179-185. https://doi.org/10.1016/0092-8674(95)90401-8
  11. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007. 1773: 1263-1284. https://doi.org/10.1016/j.bbamcr.2006.10.001
  12. Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W. Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. Biochem J. 2005. 392: 249-261. https://doi.org/10.1042/BJ20050908
  13. Pang L, Sawada T, Decker SJ, Saltiel AR. Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J Biol Chem. 1995. 270: 13585-13588. https://doi.org/10.1074/jbc.270.23.13585
  14. Pucci B, Indelicato M, Paradisi V, Reali V, Pellegrini L, Aventaggiato M, Karpinich NO, Fini M, Russo MA, Farber JL, Tafani M. ERK-1 MAP kinase prevents TNF-induced apoptosis through bad phosphorylation and inhibition of Bax translocation in HeLa Cells. J Cell Biochem. 2009. 108: 1166-1174. https://doi.org/10.1002/jcb.22345
  15. Sebolt-Leopold JS. Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway. Clin Cancer Res. 2008. 14: 3651-3656. https://doi.org/10.1158/1078-0432.CCR-08-0333
  16. Tomiyama A, Tachibana K, Suzuki K, Seino S, Sunayama J, Matsuda K-I, Sato A, Matsumoto Y, Nomiya T, Nemoto K, Yamashita H, Kayama T, Ando K, Kitanaka C. MEK-ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death. Cell Death Dis. 1, e60; doi:10.1038/cddis.2010. 37: 2010.
  17. Wong KK. Recent Developments in Anti-Cancer Agents Targeting the Ras/Raf/MEK/ERK Pathway Recent Pat. Anticancer Drug Ciscov. 2009. 4: 28-35.
  18. Yang EJ, Chang JH. Potassium cyanate induces apoptosis of human colorectal cancer cell via mitochondrial pathway. J Exp Biomed Sci. 2011. 17: 177-184.
  19. Ying TH, Yang SF, Tsai SJ, Hsieh SC, Huang YC, Bau DT, Hsieh YH. Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. 2011. (in press) https://doi.org/10.1007/s00204-011-0754-6
  20. Yuan CC, Huang HC, Tsai LC, Ng HT, Huang TS. Cytokeratin-19 associated with apoptosis and chemosensitivity in human cervical cancer cells. Apoptosis. 1997. 2: 101-105.