DOI QR코드

DOI QR Code

Thymoquinone (TQ) regulates cyclooxygenase-2 expression and prostaglandin E2 production through PI3kinase (PI3K)/p38 kinase pathway in human breast cancer cell line, MDA-MB-231

  • Yu, Seon-Mi (Department of Biological Sciences, Kongju National University) ;
  • Kim, Song-Ja (Department of Biological Sciences, Kongju National University)
  • Received : 2011.09.06
  • Accepted : 2012.12.05
  • Published : 2012.08.31

Abstract

Thymoquinone (TQ), a drug extracted from the black seeds of Nigella sativa, has been shown to exhibit anti-inflammatory, anti-oxidant, and anti-neoplastic effects in numerous cancer cells. The effects of TQ on cyclooxygenase-2 (COX-2) expression and prostaglandin $E_2$ ($PGE_2$) production in MDA-MB-231, however, remain poorly understood. Western blot analysis and immunofluorescence staining were performed to study the expression levels of inflammation regulatory proteins in MDA-MB-231. $PGE_2$ assay was conducted to explore the TQ-induced production of $PGE_2$. In this study, we investigated the effects of TQ on COX-2 expression and $PGE_2$ production in MDA-MB-231. TQ significantly induced COX-2 expression and increased $PGE_2$ production in a dose-dependent manner, as determined by a Western blot analysis and $PGE_2$ assay. Furthermore, the activation of Akt and p38 kinase, respectively, was up-regulated in TQ treated cells. Inhibition of p38 kinase with SB203580 and PI3kinase (PI3K) with LY294002 abolished TQ-caused COX-2 expression and decreased $PGE_2$ production. These results collectively demonstrate that TQ effectively modulates COX-2 expression and $PGE_2$ production via PI3K and p38 kinase pathways in the human breast cancer cell line MDA-MB-231.

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

References

  1. Ali BH, Blunden G. 2003. Pharmacological and toxicological properties of Nigella sativa. Phytother Res. 17:299-305. https://doi.org/10.1002/ptr.1309
  2. Cao Z, Liu LZ, Dixon DA, Zheng JZ, Chandran B, Jiang BH. 2007. Insulin-like growth factor-I induces cyclooxygenase- 2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells. Cell Signal. 19:1542-1553. https://doi.org/10.1016/j.cellsig.2007.01.028
  3. Costa C, Soares R, Reis-Filho JS, Leitao D, Amendoeira I, Schmitt FC. 2002. Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer. J Clin Pathol. 55:429-434. https://doi.org/10.1136/jcp.55.6.429
  4. El Mezayen R, El Gazzar M, Nicolls MR, Marecki JC, Dreskin SC, Nomiyama H. 2006. Effect of thymoquinone on cyclooxygenase expression and prostaglandin production in a mouse model of allergic airway inflammation. Immunol Lett. 106:72-81. https://doi.org/10.1016/j.imlet.2006.04.012
  5. Gali-Muhtasib H, Roessner A, Schneider-Stock R. 2006. Thymoquinone: A promising anti-cancer drug from natural sources. Int J Biochem Cell Biol. 38:1249-1253. https://doi.org/10.1016/j.biocel.2005.10.009
  6. Jemal A, Siegel R, Xu J, Ward E. 2010. Cancer statistics, 2010. CA Cancer J Clin. 60:277-300. https://doi.org/10.3322/caac.20073
  7. Lin HY, Sun M, Tang HY, Simone TM,Wu YH, Grandis JR, Cao HJ, Davis PJ, Davis FB. 2008. Resveratrol causes COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer cells. J Cell Biochem. 104:2131-2142. https://doi.org/10.1002/jcb.21772
  8. O'Banion MK. 1999. Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology. Crit Rev Neurobiol. 13:45-82. https://doi.org/10.1615/CritRevNeurobiol.v13.i1.30
  9. Park K, Han S, Shin E, Kim HJ, Kim JY. 2006. Cox-2 expression on tissue microarray of breast cancer. Eur J Surg Oncol. 32:1093-1096. https://doi.org/10.1016/j.ejso.2006.05.010
  10. Ravindran J, Nair HB, Sung B, Prasad S, Tekmal RR, Aggarwal BB. 2010. Thymoquinone poly (lactideco- glycolide) nanoparticles exhibit enhanced antiproliferative, anti-inflammatory, and chemosensitiza-tion potential. Biochem Pharmacol. 79:1640-1647. https://doi.org/10.1016/j.bcp.2010.01.023
  11. Schneider A, Stahl RA. 1998. Cyclooxygenase-2 (COX-2) and the kidney: current status and potential perspectives. Nephrol Dial Transplant. 13:10-12.
  12. Shoieb AM, Elgayyar M, Dudrick PS, Bell JL, Tithof PK. 2003. In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone. Int J Oncol. 22:107-113.
  13. Smith WL, DeWitt DL, Garavito RM. 2000. Cyclooxygenases: structural, cellular, and molecular biology. Ann Rev Biochem. 69:145-182. https://doi.org/10.1146/annurev.biochem.69.1.145
  14. Smith WL, Garavito RM, DeWitt DL. 1996. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. Critical Rev neurobiol. 271:33157-33160.
  15. Stasinopoulos I, Mori N, Bhujwalla ZM. 2008. The malignant phenotype of breast cancer cells is reduced by COX-2 silencing. Neoplasia. 10:1163-1169. https://doi.org/10.1593/neo.08568
  16. St-Germain ME, Gagnon V, Mathieu I, Parent S, Asselin E. 2004. Akt regulates COX-2 mRNA and protein expression in mutated-PTEN human endometrial cancer cells. Int J Oncol. 24:1311-1324.
  17. Takeda K, Kanekura T, Kanzaki T. 2004. Negative feedback regulation of phosphatidylinositol 3-kinase/Akt pathway by over-expressed cyclooxygenase-2 in human epidermal cancer cells. J Dermatol. 31:516-523. https://doi.org/10.1111/j.1346-8138.2004.tb00547.x
  18. Velho-Pereira R, Kumar A, Pandey BN, Jagtap AG, Mishra KP. 2011. Radiosensitization in human breast carcinoma cells by thymoquinone: role of cell cycle and apoptosis. Cell Biol Int. 35:1025-1029. https://doi.org/10.1042/CBI20100701
  19. Yang T, Huang Y, Heasley LE, Berl T, Schnermann JB, Briggs JP. 2000. MAPK mediation of hypertonicitystimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. J Biol Chem. 275:23281-23286. https://doi.org/10.1074/jbc.M910237199
  20. Yoon JH, Lim TG, Lee KM, Jeon AJ, Kim SY, Lee KW. 2011. Tangeretin reduces ultraviolet B (UVB)-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking mitogen-activated protein kinase (MAPK) activation and reactive oxygen species (ROS) generation. J Agric Food Chem. 59:222-228. https://doi.org/10.1021/jf103204x
  21. Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AM, West DW, Wu-Williams AH, Kolonel LN, Horn- Ross PL, Rosenthal JF, et al. 1993. Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst. 85:1819-1827. https://doi.org/10.1093/jnci/85.22.1819