KCl cotransport is an important modulator of human cervical cancer growth and invasion

Meng Ru Shen, Cheng Yang Chou, Keng Fu Hsu, Yueh Mei Hsu, Wen Tai Chiu, Ming Jer Tang, Seth L. Alper, J. Clive Ellory

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Cervical cancer is a major world health problem for women, but the pathophysiology of this disease has received scant attention. Here we show that the growth and invasion of cervical cancer cells are strongly linked the expression and activity of the KCl cotransporter (KCC), an important regulator of the ionic and cellular osmotic homeostasis. Functional assays of KCl cotransport activation by osmotic swelling, staurosporine, and N-ethylmaleimide indicate that removal of the N-terminal 117 amino acids from KCC1 produces a dominant-negative loss-of-function phenotype for KCl cotransport in human cervical cancer cells. The capability for regulatory volume decrease is much attenuated in the loss-of-function KCC mutant cervical cancer cells. The loss-of-function KCC mutant cervical cancer cells exhibit inhibited cell growth accompanied by decreased activity of the cell cycle gene products retinoblastoma and cdc2 kinase. Reduced cellular invasiveness is in parallel by reduced expression of αvβ3 and α 6β4 integrins, accompanied by decreased activity of matrix metalloproteinase 2 and 9. Inhibition of tumor growth in SCID mice confirms the crucial role of KCC in promoting cervical cancer growth and invasion. Thus, blockade of KCl cotransport may be a useful therapeutic adjunctive strategy to retard or prevent cervical cancer invasion.

Original languageEnglish
Pages (from-to)39941-39950
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number41
DOIs
Publication statusPublished - 2003 Oct 10

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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