Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Inhibition of thromboxane synthase activity modulates bladder cancer cell responses to chemotherapeutic agents


Recently, we reported prognostic significance of thromboxane synthase (TXAS) gene expression in invasive bladder cancer. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor metastases. In this study, using immunohistochemical analysis, we found an increased expression of TXAS protein in bladder cancer. Treatment of T24 and transitional cell carcinoma TCC-SUP bladder cancer cells with the TXAS inhibitors furegrelate or ozagrel induced an apoptotic effect measured as an increase in caspase-3 activation and cell death, and decreased survivin expression. Pharmacological inhibition of TXAS using the TXAS inhibitor furegrelate increased sensitivity to the chemotherapeutic agents cisplatin and paclitaxel. Molecular inhibition of TXAS expression by siRNA significantly decreased cell growth and migration. In concordance with the pharmacological data, siRNA-mediated reduction of TXAS expression increased sensitivity to cisplatin and paclitaxel in T24 and TCC-SUP cells. In summary, the data support a role for the thromboxane A2 pathway in the pathogenesis of bladder cancer and the potential utility of modulation of this signaling pathway for cancer chemotherapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes




  • Bando T, Fujimura M, Kasahara K, Matsuda T . (1998a). Role of thromboxane receptor on the intracellular accumulation of cis-diamminedichloroplatinum(II) in non-small-cell but not in small-cell lung cancer cell lines. Anticancer Res 18: 1079–1084.

    CAS  PubMed  Google Scholar 

  • Bando T, Fujimura M, Kasahara K, Matsuda T . (1998b). Significance of Na+, K(+)-ATPase on intracellular accumulation of cis-diamminedichloroplatinum(II) in human non-small-cell but not in small-cell lung cancer cell lines. Anticancer Res 18: 1085–1089.

    CAS  PubMed  Google Scholar 

  • Bando T, Fujimura M, Kasahara K, Shibata K, Shirasaki H, Heki U et al. (1997). Exposure to sorbitol induces resistance to cisplatin in human non-small-cell lung cancer cell lines. Anticancer Res 17: 3345–3348.

    CAS  PubMed  Google Scholar 

  • Bokemeyer C, Hartmann JT, Kuczyk MA, Truss MC, Kollmannsberger C, Beyer J et al. (1998). Recent strategies for the use of paclitaxel in the treatment of urological malignancies. World J Urol 16: 155–162.

    Article  CAS  Google Scholar 

  • Calabro F, Sternberg CN . (2002). High-risk metastatic urothelial cancer: chances for cure? Curr Opin Urol 12: 441–448.

    Article  Google Scholar 

  • Giese A, Hagel C, Kim EL, Zapf S, Djawaheri J, Berens ME et al. (1999). Thromboxane synthase regulates the migratory phenotype of human glioma cells. Neuro-oncol 1: 3–13.

    Article  CAS  Google Scholar 

  • Hour TC, Chen J, Huang CY, Guan JY, Lu SH, Hsieh CY et al. (2000). Characterization of chemoresistance mechanisms in a series of cisplatin-resistant transitional carcinoma cell lines. Anticancer Res 20: 3221–3225.

    CAS  PubMed  Google Scholar 

  • Jantke J, Ladehoff M, Kurzel F, Zapf S, Kim E, Giese A . (2004). Inhibition of the arachidonic acid metabolism blocks endothelial cell migration and induces apoptosis. Acta Neurochir (Wien) 146: 483–494.

    Article  CAS  Google Scholar 

  • Jariyawat S, Takeda M, Kobayashi M, Endou H . (1997). Thromboxane A2 mediates cisplatin-induced apoptosis of renal tubule cells. Biochem Mol Biol Int 42: 113–121.

    CAS  PubMed  Google Scholar 

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ . (2007). Cancer statistics, 2007. CA Cancer J Clin 57: 43–66.

    Article  Google Scholar 

  • Kamath K, Wilson L, Cabral F, Jordan MA . (2005). BetaIII-tubulin induces paclitaxel resistance in association with reduced effects on microtubule dynamic instability. J Biol Chem 280: 12902–12907.

    Article  CAS  Google Scholar 

  • Kasahara K, Fujimura M, Bando T, Shibata K, Shirasaki H, Matsuda T . (1996). Modulation of sensitivity to cis-diamminedichloroplatinum (II) by thromboxane A2 receptor antagonists in non-small-cell lung cancer cell lines. Br J Cancer 74: 1553–1558.

    Article  CAS  Google Scholar 

  • Kim E, Gunther W, Yoshizato K, Meissner H, Zapf S, Nusing RM et al. (2003). Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1. Oncogene 22: 7716–7727.

    Article  CAS  Google Scholar 

  • Moussa O, Yordy JS, Abol-Enein H, Sinha D, Bissada NK, Halushka PV et al. (2005). Prognostic and functional significance of thromboxane synthase gene overexpression in invasive bladder cancer. Cancer Res 65: 11581–11587.

    Article  CAS  Google Scholar 

  • Murphy S, Welk G, Thwin SS . (1990). Stimulation of thromboxane release from primary cell cultures derived from human astrocytic glioma biopsies. Glia 3: 205–211.

    Article  CAS  Google Scholar 

  • Nie D, Che M, Zacharek A, Qiao Y, Li L, Li X et al. (2004). Differential expression of thromboxane synthase in prostate carcinoma: role in tumor cell motility. Am J Pathol 164: 429–439.

    Article  CAS  Google Scholar 

  • Pascual J, Sterin-Borda L, Wald M, Borda ES . (1988). TXB2: cardiostimulant effect that involves beta-adrenoceptor and Na++K+-ATPase activity. Prostaglandins Leukot Essent Fatty Acids 33: 53–59.

    Article  CAS  Google Scholar 

  • Pradono P, Tazawa R, Maemondo M, Tanaka M, Usui K, Saijo Y et al. (2002). Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth. Cancer Res 62: 63–66.

    CAS  PubMed  Google Scholar 

  • Sakai H, Suzuki T, Takahashi Y, Ukai M, Tauchi K, Fujii T et al. (2006). Upregulation of thromboxane synthase in human colorectal carcinoma and the cancer cell proliferation by thromboxane A2. FEBS Lett 580: 3368–3374.

    Article  CAS  Google Scholar 

  • Schiff PB, Fant J, Horwitz SB . (1979). Promotion of microtubule assembly in vitro by taxol. Nature 277: 665–667.

    Article  CAS  Google Scholar 

  • Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S et al. (2001). Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19: 666–675.

    Article  CAS  Google Scholar 

  • Wald M, Pascual J, Sterin-Borda L . (1989). Role of thromboxanes in alterations of the diabetic beta-adrenergic system. Biochem Pharmacol 38: 3347–3355.

    Article  CAS  Google Scholar 

  • Watkins G, Douglas-Jones A, Mansel RE, Jiang WG . (2005). Expression of thromboxane synthase, TBXAS1 and the thromboxane A2 receptor, TBXA2R, in human breast cancer. Int Semin Surg Oncol 2: 23.

    Article  Google Scholar 

  • Winston JA, Safirstein R . (1985). Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat. Am J Physiol 249: F490–F496.

    Article  CAS  Google Scholar 

  • Yoshizato K, Zapf S, Westphal M, Berens ME, Giese A . (2002). Thromboxane synthase inhibitors induce apoptosis in migration-arrested glioma cells. Neurosurgery 50: 343–354.

    PubMed  Google Scholar 

Download references


We acknowledge the technical assistance of Alex McPherson, Margaret Romano (Hollings Cancer Center Tumor Bank) and Rick Peppler (Flow Cytometry Facility).

Author information

Authors and Affiliations


Corresponding author

Correspondence to O Moussa.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Moussa, O., Riker, J., Klein, J. et al. Inhibition of thromboxane synthase activity modulates bladder cancer cell responses to chemotherapeutic agents. Oncogene 27, 55–62 (2008).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


This article is cited by


Quick links