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

36 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

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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