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- Title
IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness.
- Authors
Yueh-Mei Hsu; Cheng-Yang Chou; Chen, Helen H. W.; Wen-Ying Lee; Yih-Fung Chen; Pin-Wen Lin; Alper, Seth L.; Ellory, J. Clive; Meng-Ru Shen
- Abstract
The cellular function of electroneutral K-Cl cotransport (KCC) is to regulate epithelial ion transport and osmotic homeostasis. Here we investigate the mechanisms by which insulin-like growth factor 1 (IGF-1) cooperates with KCC to modulate breast cancer biology. IGF-1 stimulates KCC activity of MCF-7 breast cancer cells in a dose- and time-dependent manner. Increased KCC3 and KCC4 abundances contribute to IGF-1-enhanced KCC activity. Endogenous cellular invasiveness was modestly attenuated by KCC4-specific siRNA and the residual invasiveness was much less sensitive to IGF-1 stimulation. KCC3 knockdown significantly reduced basal growth rate and almost abolished IGF-1-stimulated cell proliferation. Consistently, MCF-7 cells obtained advantage in cell proliferation and invasiveness by overexpression of KCC3 and KCC4, respectively. Blockade of gene transcription by actinomycin D abolished IGF-1-mediated increase in KCC3 and KCC4 mRNA, indicating that IGF-1 increases KCC abundance through the regulation of KCC genes. IGF-1 treatment triggered phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) cascades which were differentially required for IGF-1-stimulated biosynthesis of KCC3 and KCC4. Loss-of-function mutations in KCC significantly inhibited the development and progression of xenograft tumor in SCID mice. The expression level of IGF-1 and KCC polypeptides in the surgical specimens showed a good linear correlation, suggesting autocrine or paracrine IGF-1 stimulation of KCC production in vivo. Among patients with early-stage node-negative breast cancer, disease-free survival (DFS) and overall survival (OS) curves were significantly different based on IGF-1 and KCC expression. Thus, we conclude that KCC activation by IGF-1 plays an important role in IGF-1 receptor signaling to promote growth and spread of breast cancer cells. J. Cell. Physiol. 210: 626–636, 2007. © 2006 Wiley-Liss, Inc.
- Publication
Journal of Cellular Physiology, 2007, Vol 210, Issue 3, p626
- ISSN
0021-9541
- Publication type
Academic Journal
- DOI
10.1002/jcp.20859