title: Up-regulation of Kv7.1 channels in thromboxane A2-induced colonic cancer cell proliferation.
abstract: Thromboxane A2 (TXA2) is known to stimulate colonic cancer cell proliferation, although the mechanism has not been clarified. In this study, we compared the expression levels of Kv7.1 K(+) channels between human colorectal cancer tissue and the accompanying non-tumor mucosa. Kv7.1 proteins were found to be consistently up-regulated in the cancer tissues from different patients. Kv7.1 was also expressed in human colonic cancer cell lines. Treatment of colonic cancer cells with 9,11-epithio-11,12-methano-thromboxane A2 (STA2), a stable analogue of TXA2, significantly increased whole-cell K(+) currents sensitive to chromanol 293B, an inhibitor of Kv7.1 channels, in parallel with an increased expression of Kv7.1 proteins. In contrast, TXB2, an inactive metabolite of TXA2, had no effects on expression level and function of Kv7.1. A TXA2 receptor antagonist (SQ29548) and an inhibitor of cAMP-dependent protein kinase (Rp-8-Br-MB-cAMPS) inhibited STA2-induced increases in both Kv7.1 expression and chromanol 293B-sensitive K(+) currents. Interestingly, STA2-stimulated proliferation of colonic cancer cells was inhibited by chromanol 293B. These results suggest that Kv7.1 channels are involved in the TXA2-induced cancer cell proliferation and that they are up-regulated by the TXA2 receptor-mediated cAMP pathway.
authors.affiliation: Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takuto
authors.initials: T
authors.lastname: Fujii
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masashi
authors.initials: M
authors.lastname: Ukai
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tauchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Horikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukada
authors.forename: Hideki
authors.initials: H
authors.lastname: Sakai
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D047428:Protein Kinase Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013929:Thromboxane B2; D013928:Thromboxane A2