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

Previous work from our laboratory has shown that human ether 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- I (IGF- 1), which is known to stimulate cell proliferation. Acute applications of IGF- I increased K+ current-density and hyperpolarized MCF7 cells. The effects of IGF- I were inhibited by hEAG inhibitors. Moreover, IGF- I 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- I is inhibited pharmacologically by Asternizole or Quinidine or more specifically using siRNA against hEAG channel. Either mitogen -activated protein kinase (MAPK) or phosphaticlylinositol 3-kinase (PI3K) are known to mediate IGF- I cell proliferative signals through the activation of extracellular signal-regulated kinase 1/2 (Erk 1/2) and Akt, respectively. In MCF-7 cells, IGF- I rapidly stimulated Akt phosphorylation, whereas IGF- I 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- I 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- I increases both the activity and the expression of hEAG channels through an Akt-depenclent pathway. Since a hEAG channel is necessary for cell proliferation, its regulation by IGF- I may thus play an important role in IGF- I signaling to promote a mitogenic effect in breast cancer cells.