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

✍ Scribed by Anne-Sophie Borowiec; Frédéric Hague; Noria Harir; Stéphanie Guénin; François Guerineau; Fabrice Gouilleux; Morad Roudbaraki; Kaiss Lassoued; Halima Ouadid-Ahidouch

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 381 KB
• Volume: 212
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21065

✦ Synopsis

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. J. Cell. Physiol. 212:690–701, 2007. © 2007 Wiley‐Liss, Inc.