IGF-1 activates hEAG k+ channels through an akt-dependent signaling pathway in breast cancer cells:: Role in cell proliferation
IGF-1 activates hEAG k+ channels through an akt-dependent signaling pathway in breast cancer cells:: Role in cell proliferation
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DOI：
10.1002/jcp.21065
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发表时间：
2007-09-01
影响因子：
5.6
通讯作者：
Ouadid-Ahidouch, Halima
中科院分区：
文献类型：
--
作者：
Borowiec, Anne-Sophie;Hague, Frederic;Ouadid-Ahidouch, Halima
我们实验室以前的工作表明，人类乙醚go-go（hEAG）K+通道对乳腺癌细胞增殖和细胞周期进程至关重要。在这项研究中，我们研究了胰岛素样生长因子- I（IGF- 1），这是已知的刺激细胞增殖的hEAG通道的调节。急性应用IGF-I可增加MCF 7细胞的K+电流密度和超极化。IGF-Ⅰ的作用可被hEAG抑制剂所抑制. IGF-1还能促进hEAG mRNA的表达，并呈时间依赖性，同时促进细胞增殖。IGF-1诱导的MCF-7细胞增殖可被Asternizole或Quinidine抑制，或更特异地使用针对hEAG通道的siRNA抑制。已知丝裂原活化蛋白激酶（MAPK）或磷脂酰肌醇3-激酶（PI 3 K）分别通过激活细胞外信号调节激酶1/2（Erk 1/2）和Akt介导IGF-1细胞增殖信号。在MCF-7细胞中，IGF-Ⅰ迅速刺激Akt磷酸化，而IGF-Ⅰ对Erk 1/2几乎没有刺激作用，Erk 1/2似乎是组成性激活的。应用渥曼青霉素可阻断IGF-Ⅰ对K+电流的作用.此外，通过应用渥曼青霉素或通过特异性降低Akt激酶活性来抑制Akt磷酸化降低了hEAG mRNA水平。综上所述，我们的结果首次表明，IGF-I通过Akt依赖性途径增加hEAG通道的活性和表达。由于hEAG通道是细胞增殖所必需的，因此IGF-I对其的调节可能在IGF-I信号传导中起重要作用，以促进乳腺癌细胞中的促有丝分裂效应。
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.