Up-regulation of Kv7.1 channels in thromboxane A₂-induced colonic cancer cell proliferation

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 TXA ₂, 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 STA ₂-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.