Abstract
Ion channels like voltage-gated ether-á-go-go (Eag1) K(+) channels or Ca(2+)-activated Cl(-) channels have been shown to support cell proliferation. Bestrophin 1 (Best1) has been proposed to form Ca(2+)-activated Cl(-) channels in epithelial cells. Here we show that original T(84) colonic carcinoma cells grow slowly (T(84)-slow) and express low amounts of Eag1 and Best1, whereas spontaneously transformed T(84) cells grow fast (T(84)-fast) and express high levels of both proteins. Both Eag1 and Best1 currents are up-regulated in T(84)-fast cells. Eag1 currents were cell cycle-dependent with up-regulation during G(1)/S transition. T(84)-slow, but not T(84)-fast, cells formed tight monolayers when grown on permeable supports. RNA interference inhibition of Eag1 and Best1 reduced proliferation of T(84)-fast cells, whereas overexpression of Best1 turned T(84)-slow into fast-growing cells. Eag1 and Best1 improve intracellular Ca(2+) signaling and cell volume regulation. These results establish a novel role for bestrophins in cell proliferation.
Highlights
IntroductionBest currents are up-regulated in T84-fast cells. Eag currents were cell cycle-dependent with up-regulation during G1/S transition
bestrophin 1 (Best1) currents are up-regulated in T84-fast cells
In the present report we demonstrate that both voltage-gated Eag1 Kϩ channels and bestrophin 1 (Best1) ClϪ channels support proliferation of fast-growing T84 colonic carcinoma cells
Summary
Best currents are up-regulated in T84-fast cells. Eag currents were cell cycle-dependent with up-regulation during G1/S transition. Eag and Best improve intracellular Ca2؉ signaling and cell volume regulation These results establish a novel role for bestrophins in cell proliferation. Bestrophins have been proposed to function as regulators of voltage-gated L-type Ca2ϩ channels [14]. Our own ongoing work in epithelial cells supports both concepts, in that bestrophins may form part of a ClϪ channel complex or may couple intracellular Ca2ϩ signals to ClϪ channels of unknown molecular identity [15]. In the present report we demonstrate that both voltage-gated Eag Kϩ channels and bestrophin 1 (Best1) ClϪ channels support proliferation of fast-growing T84 colonic carcinoma cells. A recent study demonstrates the hyperpolarizing effects of Eag and other Kv channels on the membrane voltage of T84 cells, which supports intracellular pH regulation and Ca2ϩ increase necessary for proliferation [6]
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