Abstract
Thromboxane synthase (TXS), a downstream enzyme of cyclooxygenase-2, catalyses the conversion of prostaglandin H2 to thromboxane A2 (TXA2), which has been shown to induce platelet aggregation and vasoconstriction. We found that irinotecan, an antitumor drug, indirectly stimulates Cl− secretion in isolated rat colonic mucosa via release of TXA2 from the subepithelial layer. We also found recently that platelet activating factor causes the TXA2-mediated Cl− secretion in the rat colon. Herein we investigated whether TXS and TXA2 are related to human colorectal cancers. The specimens were obtained from surgical resection of patients in accordance with the recommendations of the Declaration of Helsinki. Informed consents were obtained from all patients at Toyama Medical and Pharmaceutical University Hospital. We found that both mRNA and protein of TXS were highly expressed in human colorectal carcinoma, and its expression was associated with that of transcription factor NF-E2. TXS was also highly expressed in human colonic cancer cell lines such as HT-29, KM12-L4, T-84 and WiDr. In KM12-L4 cells, the cell proliferation was significantly inhibited by the disruption of TXS protein by a specific antisense oligonucleotide. Direct addition of STA2, a stable analogue of TXA2, accelerated the proliferation the cells. After the disruption of TXS protein in the KM12-L4 cells, STA2 still induced the cell proliferation. These results suggest that TXA2 is involved in the formation of human colorectal cancer. [Jpn J Physiol 54 Suppl:S60 (2004)]
