title: Insulin-like growth factor 1 stimulates KCl cotransport, which is necessary for invasion and proliferation of cervical cancer and ovarian cancer cells.
abstract: The mechanisms by which insulin-like growth factor 1 (IGF-1) cooperates with membrane ion transport system to modulate epithelial cell motility and proliferation remain poorly understood. Here, we investigated the role of electroneutral KCl cotransport (KCC), in IGF-1-dependent invasiveness and proliferation of cervical and ovarian cancer cells. IGF-1 increased KCC activity and mRNA expression in a dose- and time-dependent manner in parallel with the enhancement of regulatory volume decrease. IGF-1 treatment triggers phosphatidylinositol 3-kinase and mitogen-activated protein kinase cascades leading to the activation of Akt and extracellular signal-regulated kinase1/2 (Erk1/2), respectively. The activated Erk1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways are differentially required for IGF-1-stimulated biosyn-thesis of KCC polypeptides. Specific reduction of Erk1/2 protein levels with small interference RNA abolishes IGF-1-stimulated KCC activity. Pharmacological inhibition and genetic modification of KCC activity demonstrate that KCC is necessary for IGF-1-induced cancer cell invasiveness and proliferation. IGF-1 and KCC colocalize in the surgical specimens of cervical cancer (n = 28) and ovarian cancer (n = 35), suggesting autocrine or paracrine IGF-1 stimulation of KCC production. Taken together, our results indicate that KCC activation by IGF-1 plays an important role in IGF-1 signaling to promote growth and spread of gynecological cancers.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Shen
authors.forename: Ai-Chien
authors.initials: AC
authors.lastname: Lin
authors.forename: Yueh-Mei
authors.initials: YM
authors.lastname: Hsu
authors.forename: Tsui-Jung
authors.initials: TJ
authors.lastname: Chang
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: J Clive
authors.initials: JC
authors.lastname: Ellory
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Chou
mesh_terms: D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011189:Potassium Chloride / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D014882:Water-Electrolyte Balance / Q000502:physiology; D000096922:K Cl- Cotransporters
chemical_list: D007334:Insulin-Like Growth Factor I; D011189:Potassium Chloride; D012333:RNA, Messenger; D027981:Symporters; D000096922:K Cl- Cotransporters; C119650:SLC12A6 protein, human; C119651:SLC12A7 protein, human