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Inhibitory effect of celecoxib in lung carcinoma by regulation of cyclooxygenase-2/cytosolic phospholipase A2 and peroxisome proliferator-activated receptor gamma

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Abstract

Celecoxib is a potent nonsteroid anti-inflammatory drug (NSAID) that has demonstrated great promise in cancer chemoprevention and treatment. The goal of this study was to determine the inhibitory effect and mechanism of celecoxib on Lewis lung carcinoma. The effect of celecoxib on viability of Lewis lung carcinoma cells was assessed with methyl thiazolyl tetrazolium (MTT) assay. Apoptosis and the mitochondrial membrane potential were detected by flow cytometric assay. The protein expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), and peroxisome proliferator-activated receptor gamma (PPARγ) were determined by Western blot analysis. The concentrations of arachidonic acid (AA) and prostaglandin E2 (PGE2) in culture supernatants were measured by the methods of RP-HPLC and PGE2-specific ELISA, respectively. Celecoxib inhibited the proliferation of Lewis lung carcinoma and induced apoptosis in a dose-dependent manner by breakdown of mitochondrial membrane potential. The protein expressions of cPLA2 and PPARγ were upregulated, but COX-2 protein expression was downregulated in the Lewis lung carcinoma cells exposed to celecoxib. The amount of AA was increased and PGE2 was decreased in the culture supernatant, respectively. The ratio of AA to PGE2 was increased in a dose-dependent manner. The major findings in this study are that celecoxib could inhibit the viability of Lewis lung carcinoma cells by interference of the AA pathway and upregulation of PPARγ simultaneously, which are novel and important since the molecular mechanisms of celecoxib underlying the anti-neoplastic effects remain unclear.

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References

  1. Matsuyama M, Yoshimura R (2009) Arachidonic acid pathway: a molecular target in human testicular cancer. Mol Med Rep 2:527–531

    CAS  Google Scholar 

  2. Matsuyama M, Yoshimura R (2008) The target of arachidonic acid pathway is a new anticancer strategy for human prostate cancer. Biologics 2:725–732

    PubMed  CAS  Google Scholar 

  3. Avis I, Martinez A, Tauler J et al (2005) Inhibitors of the arachidonic acid pathway and peroxisome proliferator-activated receptor ligands have superadditive effects on lung cancer growth inhibition. Cancer Res 65:41–90

    Article  Google Scholar 

  4. Wu T (2006) Cyclooxygenase-2 in hepatocellular carcinoma. Cancer Treat Rev 32:28–44

    Article  PubMed  CAS  Google Scholar 

  5. Yoshimatsu K, Altorki NK, Golijanin D et al (2001) Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res 7:2669–2674

    PubMed  CAS  Google Scholar 

  6. Hida T, Yatabe Y, Achiwa H et al (1998) Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 58:3761–3764

    PubMed  CAS  Google Scholar 

  7. Soslow RA, Dannenberg AJ, Rush D et al (2000) COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89:2637–2645

    Article  PubMed  CAS  Google Scholar 

  8. Gupta S, Srivastava M, Ahmad N et al (2000) Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 42:73–78

    Article  PubMed  CAS  Google Scholar 

  9. Sano H, Kawahito Y, Wilder RL et al (1995) Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55:3785–3789

    PubMed  CAS  Google Scholar 

  10. Hwang D, Scollard D, Byrne J et al (1998) Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst 90:455–460

    Article  PubMed  CAS  Google Scholar 

  11. Fosslien E (2000) Molecular pathology of cyclooxygenase-2 in neoplasia. Ann Clin Lab Sci 30:3–21

    PubMed  CAS  Google Scholar 

  12. Tang X, Sun YJ, Half E et al (2002) Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells. Cancer Res 62:4903–4908

    PubMed  CAS  Google Scholar 

  13. Nzeako UC, Guicciardi ME, Yoon JH et al (2002) COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells. Hepatology 35:552–559

    Article  PubMed  CAS  Google Scholar 

  14. Chen WS, Wei SJ, Liu JM et al (2001) Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. Int J Cancer 91:894–899

    Article  PubMed  CAS  Google Scholar 

  15. Tomozawa S, Tsuno NH, Sunami E et al (2000) Cyclooxygenase-2 overexpression correlates with tumour recurrence, especially haematogenous metastasis, of colorectal cancer. Br J Cancer 83:324–328

    Article  PubMed  CAS  Google Scholar 

  16. Leahy KM, Koki AT, Masferrer JL (2000) Role of cyclooxygenases in angiogenesis. Curr Med Chem 7:1163–1170

    PubMed  CAS  Google Scholar 

  17. Nakanishi M, Rosenberg DW (2006) Roles of cPLA2alpha and arachidonic acid in cancer. Biochim Biophys Acta 1761:1335–1343

    PubMed  CAS  Google Scholar 

  18. Li B, Gu L, Zhang H, Huang J et al (2007) Up-regulation of cPLA(2) gene expression in astrocytes by all three conventional anti-bipolar drugs is drug-specific and enzyme-specific. Psychopharmacology (Berl) 194:333–345

    Article  CAS  Google Scholar 

  19. Sertznig P, Seifert M, Tilgen W et al (2007) Present concepts and future outlook: function of peroxisome proliferator-activated receptors (PPARs) for pathogenesis, progression, and therapy of cancer. J Cell Physiol 212:1–12

    Article  PubMed  CAS  Google Scholar 

  20. Keshamouni VG, Han S, Roman J (2007) Peroxisome proliferator-activated receptors in lung cancer. PPAR Res 2007:90289

    PubMed  Google Scholar 

  21. Wang T, Xu J, Yu X et al (2006) Peroxisome proliferator-activated receptor gamma in malignant diseases. Crit Rev Oncol Hematol 58:1–14

    Article  PubMed  Google Scholar 

  22. Han S, Roman J (2007) Peroxisome proliferator-activated receptor gamma: a novel target for cancer therapeutics? Anticancer Drugs 18:237–244

    Article  PubMed  CAS  Google Scholar 

  23. Tian L, Zhou J, Casimiro MC et al (2009) Activating peroxisome proliferator-activated receptor gamma mutant promotes tumor growth in vivo by enhancing angiogenesis. Cancer Res 69:9236–9244

    Article  PubMed  CAS  Google Scholar 

  24. Evans NP, Misyak SA, Schmelz EM et al (2010) Conjugated linoleic acid ameliorates inflammation-induced colorectal cancer in mice through activation of PPARgamma. J Nutr 140:515–521

    Article  PubMed  CAS  Google Scholar 

  25. Masferrer JL, Leahy KM, Koki AT et al (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311

    PubMed  CAS  Google Scholar 

  26. Blumenthal RD, Waskewich C, Goldenberg DM et al (2001) Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenografts. Clin Cancer Res 7:3178–3185

    PubMed  CAS  Google Scholar 

  27. Williams CS, Watson AJ, Sheng H et al (2000) Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 60:6045–6051

    PubMed  CAS  Google Scholar 

  28. Liu XH (2000) Inhibition of cyclooxgenase-2 suppresses angiogenesis and the growth of prostate cancer invivo. J Urol 164:820–825

    Article  PubMed  CAS  Google Scholar 

  29. Waskewich C, Blumenthal RD, Li H et al (2002) Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines. Cancer Res 62:2029–2033

    PubMed  CAS  Google Scholar 

  30. Blaine SA, Wick M, Dessev C et al (2001) Induction of cPLA2 in lung epithelial cells and non-small cell lung cancer is mediated by Sp1 and c-Jun. J Biol Chem 276:42737–44243

    Article  PubMed  CAS  Google Scholar 

  31. Shaik MS, Chatterjee A, Jackson T et al (2006) Enhancement of antitumor activity of docetaxel by celecoxib in lung tumors. Int J Cancer 118:396–404

    Article  PubMed  CAS  Google Scholar 

  32. Scorrano L, Penzo D, Petronilli V et al (2001) Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha apoptotic signaling. J Biol Chem 276:12035–12040

    Article  PubMed  CAS  Google Scholar 

  33. Theocharis S, Kanelli H, Politi E et al (2002) Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade. Lung Cancer 36:249–255

    Article  PubMed  Google Scholar 

  34. Han S, Roman J (2006) Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. Mol Cancer Ther 5:430–437

    Article  PubMed  CAS  Google Scholar 

  35. Hazra S, Batra RK, Tai HH et al (2007) Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase. Mol Pharmacol 71:1715–1720

    Article  PubMed  CAS  Google Scholar 

  36. Krey G, Braissant O, L’Horset F et al (1997) Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 11:779–791

    Article  PubMed  CAS  Google Scholar 

  37. Lehmann JM, Lenhard JM, Oliver BB et al (1997) Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 272:3406–3410

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant from the development plan project of Jilin provincial science and technology department of China (200705163).

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Authors and Affiliations

  1. Department of Pharmacology, Norman Bethune College of Medicine, Jilin University, No. 2, Xinmin Street, Changchun, Jilin, People’s Republic of China

    Ming Zhang, Zhi-Gang Xu, Zhuo Shi, Dan Shao, Ou Li, Wei Li & Li Chen

  2. Department of Thoracic Surgery, First Hospital of Jilin University, No. 2, Xinmin Street, Changchun, Jilin, People’s Republic of China

    Zhi-Jun Li & Kai-Zhong Wang

  3. College of Chinese Material Medicine, Jilin Agricultural University, Changchun, 130118, People’s Republic of China

    Wei Li

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  1. Ming Zhang
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Correspondence to Zhi-Jun Li or Li Chen.

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Ming Zhang and Zhi-Gang Xu contribute equally to this work.

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Zhang, M., Xu, ZG., Shi, Z. et al. Inhibitory effect of celecoxib in lung carcinoma by regulation of cyclooxygenase-2/cytosolic phospholipase A2 and peroxisome proliferator-activated receptor gamma. Mol Cell Biochem 355, 233–240 (2011). https://doi.org/10.1007/s11010-011-0859-5

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  • DOI: https://doi.org/10.1007/s11010-011-0859-5

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