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 A(2) pathway in the pathogenesis of bladder cancer and the potential utility of modulation of this signaling pathway for cancer chemotherapy.
Moussa
O
O
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
Riker
J M
JM
Klein
J
J
Fraig
M
M
Halushka
P V
PV
Watson
D K
DK
D000970:Antineoplastic Agents / Q000633:toxicity*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000633:toxicity; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D013930:Thromboxane-A Synthase; D017239:Paclitaxel; D002945:Cisplatin