Research Article
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Acibenzolar-S-Methyl Inhibits MEK1/2 Signaling in SH-SY5Y Neuroblastoma Cells

Year 2019, Volume: 78 Issue: 2, 83 - 88, 06.12.2019

Abstract

Objective: Targeted cancer therapy using targeted cell proliferation inhibitors has become increasingly more critical. Studies conducted over the last decade have shown that non-steroidal drugs containing salicylic acid (SA) such as aspirin reduce mortality in many cancers. From this perspective, there are data suggesting SA as a potential inhibitor of the mitogenic MEK1/2 (mitogen-activated-protein-kinase, MAPK), extracellular-signal regulated-protein-kinase (ERK)) signaling, which could be highly effective in the prevention of proliferation in cancer. To date, no study has been conducted on the effect of SA on MEK1/2 signaling in neuroblastoma cells. Thus, the aim of this study is to reveal whether SA has an effect on MEK1/2 signaling in neuroblastoma cancer which is a frequent pediatric cancer with poor prognosis. Materials and Methods: The purpose of this study was to investigate whether a SA analog acibenzolar-S-methyl had an effect on the MEK1/2 signaling pathway and on cell viability in SH-SY5Y neuroblastoma cells by MTS (3-(4,5-dimethylthiazol2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cell viability analysis and MEK1/2 and active caspase-3 detection by western blotting technique. Results: MTS cell viability test indicated that 10 mM acibenzolar-S-methyl reduces cell viability by 50%. Western blotting results of 10 mM acibenzolar-S-methyl–treated cells showed that MEK1/2 signaling was significantly inhibited in SH-SY5H cells. Besides, an increase in active-caspase-3 levels provided insight into acibenzolar-S-methyl’s apoptotic effect which needs further morphological apoptotic data. Conclusion: Our research is the first to show that SA analog acibenzolar-S-methyl negatively affects MEK1/2 signaling causing the death of SH-SY5Y neuroblastoma cells. Our results can give insight not only into understanding the mechanisms of carcinogenesis but also into developing effective treatment methods. 

Supporting Institution

This study was supported by grant to Ayşegül Yıldız from Mugla Sitki Kocman University Scientific Research Project Office, Research and Development Projects.

Project Number

17/023

Thanks

I would like to thank Assoc.Prof.Dr. Esin Sakallı ÇETİN from Muğla Sıtkı Koçman University, Faculty of Medicine, Medical Biology Department and Prof. Dr. Arzu KARABAY KORKMAZ from lstanbul Technical University, Faculty of Science and Letters, Molecular Biology and Genetics Department for allowing me to use their laboratory infrastructure. I also would like to thank Prof. Dr. Ömür BAYSAL from Muğla Sıtkı Koçman University, Faculty of Science, Molecular Biology and Genetics Department for his generous gift of acibenzolar-S-methyl (Syngenta).

References

  • 1. Çoban ZD, Güran Ş. The role of signal transducing mechanisms in cancer diagnosis and treatment. Cumhuriyet Medical Journal 2013; 35: 302-10.
  • 2. Brasky TM, Bonner MR, Moysich KB, Ambrosone CB, Nie J, Tao MH. Non steroidal anti-inflammatory drug use (NSAID) and breast cancer risk in the western New York Exposures and breast cancer (WEB) study. Cancer Causes Control 2010; 9: 1503-12.
  • 3. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of Daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379:1591-601.
  • 4. Elwood PC, Morgan G, Pickering JE, Galante J,Weightman AL, Morris D, Kelson M, Dolwani S. Aspirin in the treatment of cancer: reductions in metastatic spread and in mortality: a systematic review and meta-analyses of published studies. PLoS One. 2016; 11(4): e0152402. doi:10.1371/ journal.pone.0152402
  • 5. Klessig DF. Newly identified targets of aspirin and its primary metabolite, salicylic acid. DNA Cell Biol 2016; 35(4):163–6. doi:10. 1089/dna.2016.3260
  • 6. Giampieri R, Restivo A, Pusceddu V, Del Prete M, Maccaroni E, Bittoni A, Faloppi L, Andrikou K, Bianconi M, Cabras F, Berardi R, Zorcolo L, Scintu F, Cascinu S, Scartozzi M. The role of aspirin as antitumoral agent for heavily pretreated patients with metastatic colorectal cancer receiving capecitabine monotherapy. Clin Colorectal Cancer 2016;16(1):38-43. doi:10.1016/j.clcc.2016.07.011
  • 7. Liu Y, Wang Y, Li L, Hu Y, Ge S, Li K, Wang S. The apoptotic inducible effects of salicylic asid on hepatoma cell line: relationship with nitric oxide signaling. J Cell Commun Signal 2017; 11: 245-53.
  • 8. Elder DJ, Hague A, Hicks DJ, Paraskeva C. Differential Growth Inhibition by the aspirin metabolite salicylate in human colorectal tumor cell lines: Enhanced apoptosis in carcinoma and in vitro-transformed adenoma relative to adenoma cell lines. Cancer Research 1996; 56: 2273-76.
  • 9. Pan MR, Chang HC, Hung WC. Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cell Signal 2008; 20(6):1134-41.
  • 10. Haydn JM, Hufnagel A, Grimm J, Maurus K, Schartl M, Meierjohann S. The MAPK pathway as an apoptosis enhancer in melanoma. Oncotarget 2014; 5(13): 5040-53.
  • 11. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007;26(22):3279-90.
  • 12. Mattingly RR, Milstein ML, Mirkin BL. Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells. Cell Signal 2001; 13(7):499-505.
  • 13. Maris JM. Recent advances in neuroblastoma. N Engl J Med 2010; 362(23):2002.
  • 14. Lubanska D, Market B, de Calvalho A., Mikkelson T, Fidalgo da Silva E, Porter LA. The atypical cell cycle regulator Spy1 suppresses differentiation of the neuroblastoma stem cell population. Oncoscience 2014; 25: 64-7.
Year 2019, Volume: 78 Issue: 2, 83 - 88, 06.12.2019

Abstract

Project Number

17/023

References

  • 1. Çoban ZD, Güran Ş. The role of signal transducing mechanisms in cancer diagnosis and treatment. Cumhuriyet Medical Journal 2013; 35: 302-10.
  • 2. Brasky TM, Bonner MR, Moysich KB, Ambrosone CB, Nie J, Tao MH. Non steroidal anti-inflammatory drug use (NSAID) and breast cancer risk in the western New York Exposures and breast cancer (WEB) study. Cancer Causes Control 2010; 9: 1503-12.
  • 3. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of Daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379:1591-601.
  • 4. Elwood PC, Morgan G, Pickering JE, Galante J,Weightman AL, Morris D, Kelson M, Dolwani S. Aspirin in the treatment of cancer: reductions in metastatic spread and in mortality: a systematic review and meta-analyses of published studies. PLoS One. 2016; 11(4): e0152402. doi:10.1371/ journal.pone.0152402
  • 5. Klessig DF. Newly identified targets of aspirin and its primary metabolite, salicylic acid. DNA Cell Biol 2016; 35(4):163–6. doi:10. 1089/dna.2016.3260
  • 6. Giampieri R, Restivo A, Pusceddu V, Del Prete M, Maccaroni E, Bittoni A, Faloppi L, Andrikou K, Bianconi M, Cabras F, Berardi R, Zorcolo L, Scintu F, Cascinu S, Scartozzi M. The role of aspirin as antitumoral agent for heavily pretreated patients with metastatic colorectal cancer receiving capecitabine monotherapy. Clin Colorectal Cancer 2016;16(1):38-43. doi:10.1016/j.clcc.2016.07.011
  • 7. Liu Y, Wang Y, Li L, Hu Y, Ge S, Li K, Wang S. The apoptotic inducible effects of salicylic asid on hepatoma cell line: relationship with nitric oxide signaling. J Cell Commun Signal 2017; 11: 245-53.
  • 8. Elder DJ, Hague A, Hicks DJ, Paraskeva C. Differential Growth Inhibition by the aspirin metabolite salicylate in human colorectal tumor cell lines: Enhanced apoptosis in carcinoma and in vitro-transformed adenoma relative to adenoma cell lines. Cancer Research 1996; 56: 2273-76.
  • 9. Pan MR, Chang HC, Hung WC. Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cell Signal 2008; 20(6):1134-41.
  • 10. Haydn JM, Hufnagel A, Grimm J, Maurus K, Schartl M, Meierjohann S. The MAPK pathway as an apoptosis enhancer in melanoma. Oncotarget 2014; 5(13): 5040-53.
  • 11. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007;26(22):3279-90.
  • 12. Mattingly RR, Milstein ML, Mirkin BL. Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells. Cell Signal 2001; 13(7):499-505.
  • 13. Maris JM. Recent advances in neuroblastoma. N Engl J Med 2010; 362(23):2002.
  • 14. Lubanska D, Market B, de Calvalho A., Mikkelson T, Fidalgo da Silva E, Porter LA. The atypical cell cycle regulator Spy1 suppresses differentiation of the neuroblastoma stem cell population. Oncoscience 2014; 25: 64-7.
There are 14 citations in total.

Details

Primary Language English
Journal Section Research Articles
Authors

Aysegul Yildiz This is me 0000-0001-6356-7459

Project Number 17/023
Publication Date December 6, 2019
Submission Date July 18, 2019
Published in Issue Year 2019 Volume: 78 Issue: 2

Cite

AMA Yildiz A. Acibenzolar-S-Methyl Inhibits MEK1/2 Signaling in SH-SY5Y Neuroblastoma Cells. Eur J Biol. December 2019;78(2):83-88.