title: IGF-1 activates hEAG K(+) channels through an Akt-dependent signaling pathway in breast cancer cells: role in cell proliferation.
abstract: Previous work from our laboratory has shown that human ether à go-go (hEAG) K(+) channels are crucial for breast cancer cell proliferation and cell cycle progression. In this study, we investigated the regulation of hEAG channels by an insulin-like growth factor-1 (IGF-1), which is known to stimulate cell proliferation. Acute applications of IGF-1 increased K(+) current-density and hyperpolarized MCF-7 cells. The effects of IGF-1 were inhibited by hEAG inhibitors. Moreover, IGF-1 increased mRNA expression of hEAG in a time-dependent manner in parallel with an enhancement of cell proliferation. The MCF-7 cell proliferation induced by IGF-1 is inhibited pharmacologically by Astemizole or Quinidine or more specifically using siRNA against hEAG channel. Either mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K) are known to mediate IGF-1 cell proliferative signals through the activation of extracellular signal-regulated kinase 1/2 (Erk 1/2) and Akt, respectively. In MCF-7 cells, IGF-1 rapidly stimulated Akt phosphorylation, whereas IGF-1 had little stimulating effect on Erk 1/2 which seems to be constitutively activated. The application of wortmannin was found to block the effects of IGF-1 on K(+) current. Moreover, the inhibition of Akt phosphorylation by the application of wortmannin or by a specific reduction of Akt kinase activity reduced the hEAG mRNA levels. Taken together, our results show, for the first time, that IGF-1 increases both the activity and the expression of hEAG channels through an Akt-dependent pathway. Since a hEAG channel is necessary for cell proliferation, its regulation by IGF-1 may thus play an important role in IGF-1 signaling to promote a mitogenic effect in breast cancer cells.
authors.affiliation: Laboratoire de Physiologie Cellulaire, EA 2086, Faculté des Sciences, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Borowiec
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hague
authors.forename: Noria
authors.initials: N
authors.lastname: Harir
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Guénin
authors.forename: François
authors.initials: F
authors.lastname: Guerineau
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gouilleux
authors.forename: Morad
authors.initials: M
authors.lastname: Roudbaraki
authors.forename: Kaiss
authors.initials: K
authors.lastname: Lassoued
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D016589:Astemizole / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010637:Phenolsulfonphthalein / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044967:Serum / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D016589:Astemizole; D051638:Ether-A-Go-Go Potassium Channels; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D010637:Phenolsulfonphthalein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011188:Potassium; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011802:Quinidine; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077191:Wortmannin