Skip to main content

Advertisement

SpringerLink
Log in

Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background

Cytotoxicity of Vitamin K3 (VK3) is indicated to have the same mechanism with oxidative stress (H2O2). In the present study, we analyzed the differences and/or similarities in the cellular responses to oxidative stress and VK3 to clarify the mechanism of growth inhibition.

Methods

Cell viability was determined by a test method with 3-[4, 5-dimethyl-thiazol]-2, 5-dephenyl tetrazolium bromide (MTT). Expressions of cellular proteins were evaluated by Western blot analysis.

Results

The IC50 was calculated to be 47.3 ± 4.1 μM for VK3 and 2.2 ± 1.2 μM for H2O2. By Western blot analysis, VK3 or H2O2 was shown to induce rapid phosphorylation of extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases (JNKs). H2O2-induced phosphorylation of ERK and JNK was almost complete inhibited by more than 100-μM genistein. VK3-induced JNK phosphorylation was blocked by 100-μM genistein, but ERK phosphorylation was not inhibited completely even if 400-μM genistein was used. H2O2-induced inhibition of cell proliferation was completely blocked by 400-μM genistein, but the VK3 effect was reduced 72.8 ± 5.4% by the same concentration of genistein. H2O2-induced JNK phosphorylation and ERK phosphorylation were inhibited by staurosporine, protein kinase C (PKC) inhibitor. VK3-induced JNK phosphorylation was also blocked, but ERK phosphorylation was not affected. Staurosporine had no effect on VK3- or H2O2-induced growth inhibition. Treatment with a non-thiol antioxidant agent, catalase, completely abrogated H2O2-induced JNK and ERK phosphorylation, but a thiol antioxidant, l-cystein, had no effect on phosphorylation of them. The VK3-induced JNK phosphorylation was inhibited by catalase, but not l-cystein. But ERK phosphorylation was not inhibited by catalase and was abrogated completely by the thiol antioxidant. Catalase, but not l-cystein, blocked H2O2-induced growth inhibition, and l-cystein, but not catalase, blocked VK3-induced effects on cell proliferation completely.

Conclusion

VK3-induced ERK phosphorylation occurs by a different mechanism from oxidative stress, and it might have an important role to induce growth inhibition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sies H (1997) Oxidative stress: oxidants and antioxidants. Exp Physiol 82:291–295

    PubMed  CAS  Google Scholar 

  2. Cuzzocrea S, Thiemermann C, Salvemini D (2004) Potential therapeutic effect of antioxidant therapy in shock and inflammation. Curr Med Chem 11:1147–1162

    PubMed  CAS  Google Scholar 

  3. Kovacic P, Jacintho JD (2001) Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer. Curr Med Chem 8:773–796

    PubMed  CAS  Google Scholar 

  4. Dong-Yun S, Yu-Ru D, Shan-Lin L, Ya-Dong Z, Lian W (2003) Redox stress regulates cell proliferation and apopstosis of human hepatoma though Akt protein phosphorylation. FEBS Lett 542:60–64

    Article  PubMed  Google Scholar 

  5. Sun Y, Oberley LW, Elwell JHm Sierra-Rivera E (1989) Antioxidant enzyme activities in normal and transformed mouse liver cells. Int J Cancer 44:1028–1033

    Article  PubMed  CAS  Google Scholar 

  6. Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192:1–15

    Article  PubMed  CAS  Google Scholar 

  7. Osada S, Imai H, Tomita H, et al (2006) Vascular endothelial growth factor protects hepatoma cells against oxidative stress-induced cell death. J Gastroenterol Hepatol 21:988–993

    Article  PubMed  CAS  Google Scholar 

  8. Dragin N, Smani M, Arnaud-Dabernat S, Dubost C, Moranvillier I, Costet P, Daniel JY, Peuchant E (2006) Acute oxidative stress is associated with cell proliferation in the mouse liver. FEBS Lett 580:3845–3852

    Article  PubMed  CAS  Google Scholar 

  9. Ma X, Du J, Nakashima I, Nagase F (2002) Menadione biphasically controls JNK-linked cell death in leukemia Jurkat T cells. Antioxid Redox Signal 4:371–378

    Article  PubMed  CAS  Google Scholar 

  10. Verrax J, Cadrobbi J, Delvaux M, Jamison JM, Gilloteaux J, Sumemrs JL (2003) The association of Vitamin C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy. Eur J Med Chem 38:451–457

    Article  PubMed  CAS  Google Scholar 

  11. DeYulia GJ Jr, Carcamo JM, Borquez-Ojeda O, Shelton CC, Golde DW (2005) Hydrogen peroxide-generated extracellularly by receptor-ligand interaction facilitates cell signaling. Proc Natl Acad Sci USA 192:5044–5049

    Article  Google Scholar 

  12. Buc Calderon P, Cadrobbi J, Marques C, Hong-Ngoc N, Jamison JM, Gilloteaux J, et al (2002) Potential therapeutic application of the association of vitamins C and K3 in cancer treatment. Curr Med Chem 9:2271–2285

    PubMed  CAS  Google Scholar 

  13. Osada S, Kanematsu M, Imai H, et al (2005) Evaluation of extracellular signal regulated kinase expression ant its relation to treatment of hepatocellular carcinoma. J Am Coll Surg 201:405–411

    Article  PubMed  Google Scholar 

  14. Lee JM, Hanson JM, Chu WA, Johnson JA (2001) Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR-32 human neuroblastoma cells. J Biol Chem 276:20011–20016

    Article  PubMed  CAS  Google Scholar 

  15. Huang HC, Nguyen T, Pickett CB (2002) Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem 277:42769–42774

    Article  PubMed  CAS  Google Scholar 

  16. Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11:211–218

    Article  PubMed  CAS  Google Scholar 

  17. Awazu M, Ishikura K, Hida M, Hoshiya M (1999) Mechanisms of mitogen-activated protein kinase activation in experimental diabetes. J Am Soc Nephrol 10:738–745

    PubMed  CAS  Google Scholar 

  18. Han HJ, Heo JS, Lee YJ, Min JJ, Park KS (2006) High glucose-induced inhibition of 2-deoxyglucose uptake is mediated by c-AMP, protein kinase C, oxidative stress and mitogen-activated protein kinases in mouse embryonic cells. Clin Exper Pharm Phys 33:211–220

    Article  CAS  Google Scholar 

  19. LeHoux JG, Lefebvre A (2006) Novel protein kinase C-epsilon inhibits human CYP11B2 gene expression through ERK 1/2 signaling pathway and JunB. J Mol Endoscin 36:51–64

    Article  CAS  Google Scholar 

  20. Malarkey K, Belham CM, Paul A, et al (1995) The regulation of tyrosine kinase signaling pathways by growth factor and G-protein-coupled receptors. Biochem J 309:361–375

    PubMed  CAS  Google Scholar 

  21. Ni CW, Wang DL, Lien SC, Cheng JJ, Chao YJ, Hsieh HJ (2003) Activation of PKC-epsilon and ERK 1/2 partcipates in shear-induced endothelial MCP-1 expression that is repressed by nitric oxide. J Cell Physiol 195:428–434

    Article  PubMed  CAS  Google Scholar 

  22. Kim KY, Choi KC, Auersperg N, Leung PC (2006) Mechanism of gonadotropin-releasing hormone (GnRH)-I and –II-induced cell growth inhibition in ovarian cancer cells: role of the GnRH-I receptor and protein kinase C pathway. Endocr Relat Cancer 13:211–220

    Article  PubMed  CAS  Google Scholar 

  23. Hecht D, Zick Y (1992) Selective inhibition of protein tyrosine phosphatase activities by H2O2 and vanadate in vitro. Biochem Biophys Res Commun 188:773–779

    Article  PubMed  CAS  Google Scholar 

  24. Nishikawa Y, Wang Z, Kerns J, Wilcox CS, Carr BI (1999) Inhibition of hepatoma cell growth in vitro by arylating and non-arylating K vitamin analogs. Significance of protein tyrosine phosphatase inhibition. J Biol Chem 274:34803–34810

    Article  PubMed  CAS  Google Scholar 

  25. Osada S, Saji S (2003) New approach to cancer therapy: the application of signal transduction to anti-cancer drug. Curr Med Chem 3:119–131

    CAS  Google Scholar 

  26. Kerns J, Naganathan S, Dowd P, Finn F, Carr BI (1995) Thioalkyl derivatives of vitamin K3 and vitamin K3 oxide inhibit growth of Hep 3B and Hep G2. Bioorg Chem 23:101–108

    Article  CAS  Google Scholar 

  27. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greengerg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331

    Article  PubMed  CAS  Google Scholar 

  28. Osada S, Saji S, Osada K (2001) Critical role of extracellular signal-regulated kinase phosphorylation on menadione (vitamin K3) induced growth inhibition. Cancer 91:1156–1165

    Article  PubMed  CAS  Google Scholar 

  29. Osada S, Carr BI (2001) Mechanism of novel vitamin K analogs induced growth inhibition in human hepatoma cell line. J Hepatol 34:676–682

    Article  PubMed  CAS  Google Scholar 

  30. Zhu L, Yu X, Akatsuka Y, Cooper JA, Anasetti C (2001) Role of mitogen-activated protein kinases in activation-induced apoptosis of T cells. Immunology 92:26–35

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Surgical Oncology, Gifu University School of Medicine, 1-1 Yanagido, Gifu city, 501-1194, Japan

    Shinji Osada, Fumio Sakashita, Yosiki Hosono, Kenichi Nonaka, Yasuharu Tokuyama, Hidenori Tanaka, Yoshiyuki Sasaki, Hiroyuki Tomita, Shuji Komori, Satoshi Matsui & Takao Takahashi

Authors
  1. Shinji Osada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fumio Sakashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yosiki Hosono
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenichi Nonaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuharu Tokuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hidenori Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiyuki Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroyuki Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shuji Komori
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Satoshi Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takao Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinji Osada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Osada, S., Sakashita, F., Hosono, Y. et al. Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells. Cancer Chemother Pharmacol 62, 315–320 (2008). https://doi.org/10.1007/s00280-007-0610-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0610-9

Keywords

Search

Navigation