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J. Biol. Chem., Vol. 279, Issue 38, 40017-40025, September 17, 2004

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Insulin-like Growth Factor 1 Stimulates KCl Cotransport, Which Is Necessary for Invasion and Proliferation of Cervical Cancer and Ovarian Cancer Cells^*

Meng-Ru Shen, Ai-Chien Lin, Yueh-Mei Hsu, Tsui-Jung Chang, Ming-Jer Tang¶, Seth L. Alper||, J. Clive Ellory**, and Cheng-Yang Chou

From the Departments of Pharmacology, Obstetrics & Gynecology, and ^¶Physiology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan, ^||Molecular and Vascular Medicine Unit and Renal Unit, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, and ^**University Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, United Kingdom

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 biosyn-thesis 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.

Received for publication, June 16, 2004 , and in revised form, July 13, 2004.

^* This work was supported in part by National Science Council, Taiwan Grants NSC93-2320-B-006-028 and NSC93-2314-B-006-020 (to M.-R. S) and Grant NSC92-2314-B-006-124 (to C.-Y. C.), National Health Research Institutes Grant NHRI-EX93-9311BS (to M.-R. S.), and Center for Bioscience and Biotechnology, National Cheng Kung University and Program for Promoting University Academic Excellence Grant 91-B-FA09-1-4 (to M.-R. S. and C.-Y. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 138 Sheng-Li Road, Tainan 704, Taiwan. Tel.: 886-6-2353535 (ext. 5608); Fax: 886-6-2766185; E-mail: chougyn{at}mail.ncku.edu.tw.

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