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Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.03.2014 | Original Paper

Thromboxane A2 exerts promoting effects on cell proliferation through mediating cyclooxygenase-2 signal in lung adenocarcinoma cells

verfasst von: Run-Yue Huang, Shan-Shan Li, Hui-Zhen Guo, Yu Huang, Xian Zhang, Ming-Yue Li, George Gong Chen, Xing Zeng

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 3/2014

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Abstract

Background

Lung cancer concerns a worldwide health problem and the efficacy of available treatments is unsatisfactory. Recently, thromboxane A2 (TXA2) synthase (TXAS) and receptor (TXA2R) have been documented to play a role in lung cancer development. Therefore, dual TXA2R modulator (i.e., the dual blocker of TXAS and TXA2R) may be more efficacious to kill lung tumor cells than single TXAS inhibitor or TXA2R antagonism. The close relationship between cyclooxygenase (COX)-2 and TXAS also raises whether or how TXA2 contributes to the oncogenic activity of COX-2. This study is therefore conducted to answer these questions.

Methods

Various inhibitors and siRNA were used to evaluate the roles of TXA2 and COX-2 in the proliferation and apoptosis of lung adenocarcinoma cells. Cell proliferation was detected using both MTS ELISA and BrdU labeling ELISA. Cell cycle distribution and apoptosis were examined by flow cytometric analysis. TXB2 level, reflecting the biosynthesis of TXA2, was detected by peroxidase-labeled TXB2 conjugates using an enzyme immunoassay kit. Western blotting was performed to evaluate many biomarkers for cell cycles, apoptosis and proliferation. The levels of COXs were screened by reverse transcriptase and real-time quantitative PCR.

Results

We found either single TXAS inhibitor/TXA2R antagonist or the dual TXA2 modulators offered a similar inhibition on cell proliferation. Moreover, inhibition of TXA2 arrested cells at the G2/M phase and induced apoptosis. It is further demonstrated that TXA2 was able to function as a critical mediator for tumor-promoting effects of COX-2 in lung adenocarcinoma cells.

Conclusion

The present study has for the first shown that dual TXA2 modulators and the single blocker of TXAS or TXA2R offer a similar inhibitory role in lung adenocarcinoma cell proliferation and that the tumor-promoting effects of COX-2 can largely be relayed by TXA2. Thus, TXA2 should be regarded as a critical molecule in COX-2-mediated tumor growth and a valuable target against lung cancer.

Abramovitz M, Adam M, Boie Y, Carriere M, Denis D, Godbout C, Lamontagne S, Rochette C, Sawyer N, Tremblay NM, Belley M, Gallant M, Dufresne C, Gareau Y, Ruel R, Juteau H, Labelle M, Ouimet N, Metters KM (2000) The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim Biophys Acta 1483(2):285–293PubMedCrossRef

Belvisi MG, Saunders M, Yacoub M, Mitchell JA (1998) Expression of cyclo-oxygenase-2 in human airway smooth muscle is associated with profound reductions in cell growth. Br J Pharmacol 125(5):1102–1108PubMedCrossRef

Brodskii V, Vasil’ev AV, Terskikh VV, Zvezdina ND, Fateeva VI, Mal’chenko LA, Kiseleva EV, Bueverova EI (2012) Mesenchymal stromal cells synchronize the rhythm of protein synthesis under the effect of an exogenous signal. Ontogenez 43(3):229–232PubMed

Cathcart MC, Reynolds JV, O’Byrne KJ, Pidgeon GP (2010) The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer. Biochim Biophys Acta 1805(2):153–166. doi:10.1016/j.bbcan.2010.01.006 PubMed

Cathcart MC, Gately K, Cummins R, Kay E, O’Byrne KJ, Pidgeon GP (2011) Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer. Mol Cancer 10:25. doi:10.1186/1476-4598-10-25 PubMedCentralPubMedCrossRef

Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A, Cramer HM, Davidson DD, Zhang S (2012) Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol 25(3):347–369. doi:10.1038/modpathol.2011.215 PubMedCrossRef

Cufer T, Ovcaricek T, O’Brien ME (2013) Systemic therapy of advanced non-small cell lung cancer: major-developments of the last 5-years. Eur J Cancer 49(6):1216–1225. doi:10.1016/j.ejca.2012.11.021 PubMedCrossRef

de Leval X, Dassesse T, Dogne JM, Waltregny D, Bellahcene A, Benoit V, Pirotte B, Castronovo V (2006) Evaluation of original dual thromboxane A2 modulators as antiangiogenic agents. J Pharmacol Exp Ther 318(3):1057–1067. doi:10.1124/jpet.106.101188 PubMedCrossRef

Ekambaram P, Lambiv W, Cazzolli R, Ashton AW, Honn KV (2011) The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis. Cancer Metastasis Rev 30(3–4):397–408. doi:10.1007/s10555-011-9297-9 PubMedCrossRef

Ermert L, Dierkes C, Ermert M (2003) Immunohistochemical expression of cyclooxygenase isoenzymes and downstream enzymes in human lung tumors. Clin Cancer Res 9(5):1604–1610PubMed

Gee J, Lee IL, Grossman HB, Sabichi AL (2008) Forced COX-2 expression induces PGE(2) and invasion in immortalized urothelial cells. Urol Oncol 26(6):641–645. doi:10.1016/j.urolonc.2007.05.015 PubMedCrossRef

Hinz B, Brune K, Pahl A (2000) Prostaglandin E(2) upregulates cyclooxygenase-2 expression in lipopolysaccharide-stimulated RAW 264.7 macrophages. Biochem Biophys Res Commun 272(3):744–748. doi:10.1006/bbrc.2000.2859 PubMedCrossRef

Huang RY, Chen GG (2011) Cigarette smoking, cyclooxygenase-2 pathway and cancer. Biochim Biophys Acta 1815(2):158–169. doi:10.1016/j.bbcan.2010.11.005 PubMed

Huang RY, Li MY, Hsin MK, Underwood MJ, Ma LT, Mok TS, Warner TD, Chen GG (2011) 4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor. Oncogene 30(1):106–116. doi:10.1038/onc.2010.390 PubMed

Huang RY, Li MY, Ng CS, Wan IY, Kong AW, Du J, Long X, Underwood MJ, Mok TS, Chen GG (2013) Thromboxane A2 receptor alpha promotes tumor growth through an autoregulatory feedback pathway. J Mol Cell Biol 5(6):380–390. doi:10.1093/jmcb/mjt038 PubMed

Kim Y-M, Pyo H (2013) Different cell cycle modulation by celecoxib at different concentrations. Cancer Biother Radiopharm 28(2):138–145PubMed

Larzabal L, Nguewa PA, Pio R, Blanco D, Sanchez B, Rodriguez MJ, Pajares MJ, Catena R, Montuenga LM, Calvo A (2011) Overexpression of TMPRSS4 in non-small cell lung cancer is associated with poor prognosis in patients with squamous histology. Br J Cancer 105(10):1608–1614. doi:10.1038/bjc.2011.432 PubMedCentralPubMed

Leung KC, Hsin MK, Chan JS, Yip JH, Li M, Leung BC, Mok TS, Warner TD, Underwood MJ, Chen GG (2009) Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27. Exp Cell Res 315(17):2974–2981. doi:10.1016/j.yexcr.2009.06.025 PubMed

Li X, Tai HH (2012) Increased expression of matrix metalloproteinases mediates thromboxane A2-induced invasion in lung cancer cells. Curr Cancer Drug Targets 12(6):703–715PubMed

Li X, Tai HH (2013) Thromboxane A receptor-mediated release of matrix metalloproteinase-1 (MMP-1) induces expression of monocyte chemoattractant protein-1 (MCP-1) by activation of protease-activated receptor 2 (PAR2) in A549 human lung adenocarcinoma cells. Mol Carcinog. doi:10.1002/mc.22020

Liu W, Chen Y, Wang W, Keng P, Finkelstein J, Hu D, Liang L, Guo M, Fenton B, Okunieff P, Ding I (2003) Combination of radiation and celebrex (celecoxib) reduce mammary and lung tumor growth. Am J Clin Oncol 26(4):S103–S109. doi:10.1097/01.COC.0000074147.22064.67 PubMed

McLemore TL, Hubbard WC, Litterst CL, Liu MC, Miller S, McMahon NA, Eggleston JC, Boyd MR (1988) Profiles of prostaglandin biosynthesis in normal lung and tumor tissue from lung cancer patients. Cancer Res 48(11):3140–3147PubMed

Minghetti L, Polazzi E, Nicolini A, Creminon C, Levi G (1997) Up-regulation of cyclooxygenase-2 expression in cultured microglia by prostaglandin E2, cyclic AMP and non-steroidal anti-inflammatory drugs. Eur J Neurosci 9(5):934–940PubMed

Moussa O, Ashton AW, Fraig M, Garrett-Mayer E, Ghoneim MA, Halushka PV, Watson DK (2008a) Novel role of thromboxane receptors beta isoform in bladder cancer pathogenesis. Cancer Res 68(11):4097–4104. doi:10.1158/0008-5472.CAN-07-6560 PubMed

Moussa O, Riker JM, Klein J, Fraig M, Halushka PV, Watson DK (2008b) Inhibition of thromboxane synthase activity modulates bladder cancer cell responses to chemotherapeutic agents. Oncogene 27(1):55–62. doi:10.1038/sj.onc.1210629 PubMed

Moussa O, Ciupek A, Watson DK, Halushka PV (2011) Urinary thromboxane B2 and thromboxane receptors in bladder cancer: opportunity for detection and monitoring. Prostaglandins Other Lipid Mediat 96(1–4):41–44. doi:10.1016/j.prostaglandins.2011.09.002 PubMedCentralPubMed

Nakahata N (2008) Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacol Ther 118(1):18–35. doi:10.1016/j.pharmthera.2008.01.001 PubMed

Nie D, Guo Y, Yang D, Tang Y, Chen Y, Wang MT, Zacharek A, Qiao Y, Che M, Honn KV (2008) Thromboxane A2 receptors in prostate carcinoma: expression and its role in regulating cell motility via small GTPase Rho. Cancer Res 68(1):115–121. doi:10.1158/0008-5472.CAN-07-1018 PubMed

Patscheke H (1990) Current concepts for a drug-induced inhibition of formation and action of thromboxane A2. Blut 60(5):261–268PubMed

Rosch S, Ramer R, Brune K, Hinz B (2005) Prostaglandin E2 induces cyclooxygenase-2 expression in human non-pigmented ciliary epithelial cells through activation of p38 and p42/44 mitogen-activated protein kinases. Biochem Biophys Res Commun 338(2):1171–1178. doi:10.1016/j.bbrc.2005.10.051 PubMed

Strillacci A, Griffoni C, Valerii MC, Lazzarini G, Tomasi V, Spisni E (2010) RNAi-based strategies for cyclooxygenase-2 inhibition in cancer. J Biomed Biotechnol 2010:828045. doi:10.1155/2010/828045 PubMedCentralPubMed

Setia S, Sanyal SN (2012) Downregulation of NF-κB and PCNA in the regulatory pathways of apoptosis by cyclooxygenase-2 inhibitors in experimental lung cancer. Mol Cell Biochem 369(1–2):75–86. doi:10.1007/s11010-012-1370-3

Su JL, Shih JY, Yen ML, Jeng YM, Chang CC, Hsieh CY, Wei LH, Yang PC, Kuo ML (2004) Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res 64(2):554–564PubMed

Wang D, Dubois RN (2006) Prostaglandins and cancer. Gut 55(1):115–122. doi:10.1136/gut.2004.047100 PubMed

Wei J, Yan W, Li X, Chang WC, Tai HH (2007) Activation of thromboxane receptor alpha induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells. Biochem Pharmacol 74(5):787–800. doi:10.1016/j.bcp.2007.06.008 PubMedCentralPubMed

Wei J, Yan W, Li X, Ding Y, Tai HH (2010) Thromboxane receptor alpha mediates tumor growth and angiogenesis via induction of vascular endothelial growth factor expression in human lung cancer cells. Lung Cancer 69(1):26–32. doi:10.1016/j.lungcan.2009.09.009 PubMed

Wu YC, Su LJ, Wang HW, Jeff Lin CF, Hsu WH, Chou TY, Huang CY, Lu CL, Hsueh CT (2010) Co-overexpression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 adversely affects the postoperative survival in non-small cell lung cancer. J Thorac Oncol 5(8):1167–1174. doi:10.1097/JTO.0b013e3181e2f4f5 PubMed

Yucel-Lindberg T, Ahola H, Carlstedt-Duke J, Modeer T (1999) Involvement of tyrosine kinases on cyclooxygenase expression and prostaglandin E2 production in human gingival fibroblasts stimulated with interleukin-1beta and epidermal growth factor. Biochem Biophys Res Commun 257(2):528–532. doi:10.1006/bbrc PubMed

Titel: Thromboxane A2 exerts promoting effects on cell proliferation through mediating cyclooxygenase-2 signal in lung adenocarcinoma cells
verfasst von: Run-Yue Huang
Shan-Shan Li
Hui-Zhen Guo
Yu Huang
Xian Zhang
Ming-Yue Li
George Gong Chen
Xing Zeng
Publikationsdatum: 01.03.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 3/2014
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-013-1573-3

Springer Medizin

Thromboxane A2 exerts promoting effects on cell proliferation through mediating cyclooxygenase-2 signal in lung adenocarcinoma cells