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IGF-1 activates hEAG K+ channels through an Akt-dependent signaling pathway in breast cancer cells: Role in cell proliferation

Abstract : Previous work from our laboratory has shown that human ether à go-go (hEAG) K+ channels are crucial for breast cancer cell proliferation and cell cycle progression. In this study, we investigated the regulation of hEAG channels by an insulin-like growth factor-1 (IGF-1), which is known to stimulate cell proliferation. Acute applications of IGF-1 increased K+ current-density and hyperpolarized MCF-7 cells. The effects of IGF-1 were inhibited by hEAG inhibitors. Moreover, IGF-1 increased mRNA expression of hEAG in a time-dependent manner in parallel with an enhancement of cell proliferation. The MCF-7 cell proliferation induced by IGF-1 is inhibited pharmacologically by Astemizole or Quinidine or more specifically using siRNA against hEAG channel. Either mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) are known to mediate IGF-1 cell proliferative signals through the activation of extracellular signal-regulated kinase 1/2 (Erk 1/2) and Akt, respectively. In MCF-7 cells, IGF-1 rapidly stimulated Akt phosphorylation, whereas IGF-1 had little stimulating effect on Erk 1/2 which seems to be constitutively activated. The application of wortmannin was found to block the effects of IGF-1 on K+ current. Moreover, the inhibition of Akt phosphorylation by the application of wortmannin or by a specific reduction of Akt kinase activity reduced the hEAG mRNA levels. Taken together, our results show, for the first time, that IGF-1 increases both the activity and the expression of hEAG channels through an Akt-dependent pathway. Since a hEAG channel is necessary for cell proliferation, its regulation by IGF-1 may thus play an important role in IGF-1 signaling to promote a mitogenic effect in breast cancer cells
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Contributor : Fabrice Gouilleux Connect in order to contact the contributor
Submitted on : Saturday, October 30, 2021 - 10:06:07 AM
Last modification on : Friday, August 5, 2022 - 11:25:06 AM
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Anne-Sophie Borowiec, Frédéric Hague, Noria Harir, Stéphanie Guénin, François Guérineau, et al.. IGF-1 activates hEAG K+ channels through an Akt-dependent signaling pathway in breast cancer cells: Role in cell proliferation. Journal of Cellular Physiology, Wiley, 2007, 212 (3), pp.690-701. ⟨10.1002/jcp.21065⟩. ⟨hal-02424608⟩



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