Insulin-like growth factor 1 stimulates KCl cotransport, which is necessary for invasion and proliferation of cervical cancer and ovarian cancer cells
Insulin-like growth factor 1 stimulates KCl cotransport, which is necessary for invasion and proliferation of cervical cancer and ovarian cancer cells
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DOI：
10.1074/jbc.m406706200
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发表时间：
2004-09-17
影响因子：
4.8
通讯作者：
Chou, CY
中科院分区：
文献类型：
--
作者：
Shen, MR;Lin, AC;Chou, CY
胰岛素样生长因子1（IGF-1）与膜离子转运系统协同调节上皮细胞运动和增殖的机制仍知之甚少。在此，我们研究了电中性KCl共转运（KCC）在IGF-1依赖的宫颈癌和卵巢癌细胞侵袭和增殖中的作用。IGF-1以剂量和时间依赖性方式增加KCC活性和mRNA表达，同时增加调节性容积减少。IGF-1治疗触发磷脂酰肌醇3-激酶和丝裂原活化蛋白激酶级联反应，分别导致Akt和细胞外信号调节激酶1/2（Erk 1/2）的活化。活化的Erk 1/2促分裂原活化蛋白激酶和磷脂酰肌醇3-激酶信号通路是IGF-1刺激的KCC多肽生物合成所需的差异。用小干扰RNA特异性降低Erk 1/2蛋白水平可消除IGF-1刺激的KCC活性。药理学抑制和KCC活性的遗传修饰表明，KCC是IGF-1诱导的癌细胞侵袭和增殖所必需的。IGF-1和KCC共定位于宫颈癌（n = 28）和卵巢癌（n = 35）的手术标本，表明自分泌或旁分泌IGF-1刺激KCC的生产。综上所述，我们的研究结果表明，IGF-1激活KCC在IGF-1信号传导中起着重要作用，以促进妇科癌症的生长和扩散。
The mechanisms by which insulin-like growth factor 1 (IGF-1) cooperates with membrane ion transport system to modulate epithelial cell motility and proliferation remain poorly understood. Here, we investigated the role of electroneutral KCl cotransport (KCC), in IGF-1-dependent invasiveness and proliferation of cervical and ovarian cancer cells. IGF-1 increased KCC activity and mRNA expression in a dose- and time-dependent manner in parallel with the enhancement of regulatory volume decrease. IGF-1 treatment triggers phosphatidylinositol 3-kinase and mitogen-activated protein kinase cascades leading to the activation of Akt and extracellular signal-regulated kinase1/2 (Erk1/2), respectively. The activated Erk1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways are differentially required for IGF-1-stimulated biosynthesis of KCC polypeptides. Specific reduction of Erk1/2 protein levels with small interference RNA abolishes IGF-1-stimulated KCC activity. Pharmacological inhibition and genetic modification of KCC activity demonstrate that KCC is necessary for IGF-1-induced cancer cell invasiveness and proliferation. IGF-1 and KCC colocalize in the surgical specimens of cervical cancer ( n = 28) and ovarian cancer ( n = 35), suggesting autocrine or paracrine IGF-1 stimulation of KCC production. Taken together, our results indicate that KCC activation by IGF-1 plays an important role in IGF-1 signaling to promote growth and spread of gynecological cancers.