IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness

Yueh Mei Hsu, Cheng-Yang Chou, Helen H.W Chen, Wen Ying Lee, Yih Fung Chen, Pin Wen Lin, Seth L. Alper, J. Clive Ellory, Meng-Ru Shen

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

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 m ice. 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.

Original languageEnglish
Pages (from-to)626-636
Number of pages11
JournalJournal of Cellular Physiology
Volume210
Issue number3
DOIs
Publication statusPublished - 2007 Mar 1

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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