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.
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We acknowledge the technical assistance of Alex McPherson, Margaret Romano (Hollings Cancer Center Tumor Bank) and Rick Peppler (Flow Cytometry Facility).
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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). https://doi.org/10.1038/sj.onc.1210629
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