KCl cotransport is an important modulator of human cervical cancer growth and invasion.
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 alpha v beta 3 and alpha 6 beta 4 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.
Shen
Meng-Ru
MR
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan. mrshen@mail.ncku.edu.tw
Chou
Cheng-Yang
CY
Hsu
Keng-Fu
KF
Hsu
Yueh-Mei
YM
Chiu
Wen-Tai
WT
Tang
Ming-Jer
MJ
Alper
Seth L
SL
Ellory
J Clive
JC
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D048429:Cell Size; D002712:Chlorides / Q000378:metabolism; D005260:Female; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D017384:Sequence Deletion; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000096922:K Cl- Cotransporters
D016203:CDC2 Protein Kinase; D002712:Chlorides; D039161:Integrin alpha6beta4; D039302:Integrin alphaVbeta3; D011188:Potassium; D016160:Retinoblastoma Protein; D027981:Symporters; D000096922:K Cl- Cotransporters