Potassium channel KCNA1 modulates oncogene-induced senescence and transformation

Hélène Lallet-Daher, Clotilde Wiel, Delphine Gitenay, Naveenan Navaratnam, Arnaud Augert, Benjamin Le Calvé, Stéphanie Verbeke, David Carling, Sébastien Aubert, David Vindrieux, David Bernard

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway.

langue originaleAnglais
Pages (de - à)5253-65
Nombre de pages13
journalCancer Research
Volume73
Numéro de publication16
Les DOIs
étatPublié - 2013
Modification externeOui

Empreinte digitale

Kv1.1 Potassium Channel
Oncogenes
Cyclic AMP-Dependent Protein Kinases
Membrane Potentials
Carcinogenesis
Cytoplasm
Neoplasms
Membranes
Cell Aging
Potassium Channels
Licensure
Phosphorylation
Breast Neoplasms
Growth

Citer ceci

Lallet-Daher, H., Wiel, C., Gitenay, D., Navaratnam, N., Augert, A., Le Calvé, B., ... Bernard, D. (2013). Potassium channel KCNA1 modulates oncogene-induced senescence and transformation. Cancer Research, 73(16), 5253-65. https://doi.org/10.1158/0008-5472.CAN-12-3690
Lallet-Daher, Hélène ; Wiel, Clotilde ; Gitenay, Delphine ; Navaratnam, Naveenan ; Augert, Arnaud ; Le Calvé, Benjamin ; Verbeke, Stéphanie ; Carling, David ; Aubert, Sébastien ; Vindrieux, David ; Bernard, David. / Potassium channel KCNA1 modulates oncogene-induced senescence and transformation. Dans: Cancer Research. 2013 ; Vol 73, Numéro 16. p. 5253-65.
@article{857420f74eb04c79a250026bada62736,
title = "Potassium channel KCNA1 modulates oncogene-induced senescence and transformation",
abstract = "Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway.",
keywords = "Animals, Breast Neoplasms, Cell Aging, Cell Growth Processes, Cell Line, Cell Membrane, Cell Transformation, Neoplastic, Cyclic AMP-Dependent Protein Kinases, Cytoplasm, Down-Regulation, Humans, Kv1.1 Potassium Channel, Mammary Glands, Human, Membrane Potentials, Mice, NIH 3T3 Cells, Phosphorylation, Signal Transduction, Journal Article, Research Support, Non-U.S. Gov't",
author = "H{\'e}l{\`e}ne Lallet-Daher and Clotilde Wiel and Delphine Gitenay and Naveenan Navaratnam and Arnaud Augert and {Le Calv{\'e}}, Benjamin and St{\'e}phanie Verbeke and David Carling and S{\'e}bastien Aubert and David Vindrieux and David Bernard",
year = "2013",
doi = "10.1158/0008-5472.CAN-12-3690",
language = "English",
volume = "73",
pages = "5253--65",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

Lallet-Daher, H, Wiel, C, Gitenay, D, Navaratnam, N, Augert, A, Le Calvé, B, Verbeke, S, Carling, D, Aubert, S, Vindrieux, D & Bernard, D 2013, 'Potassium channel KCNA1 modulates oncogene-induced senescence and transformation', Cancer Research, VOL. 73, Numéro 16, p. 5253-65. https://doi.org/10.1158/0008-5472.CAN-12-3690

Potassium channel KCNA1 modulates oncogene-induced senescence and transformation. / Lallet-Daher, Hélène; Wiel, Clotilde; Gitenay, Delphine; Navaratnam, Naveenan; Augert, Arnaud; Le Calvé, Benjamin; Verbeke, Stéphanie; Carling, David; Aubert, Sébastien; Vindrieux, David; Bernard, David.

Dans: Cancer Research, Vol 73, Numéro 16, 2013, p. 5253-65.

Résultats de recherche: Contribution à un journal/une revueArticle

TY - JOUR

T1 - Potassium channel KCNA1 modulates oncogene-induced senescence and transformation

AU - Lallet-Daher, Hélène

AU - Wiel, Clotilde

AU - Gitenay, Delphine

AU - Navaratnam, Naveenan

AU - Augert, Arnaud

AU - Le Calvé, Benjamin

AU - Verbeke, Stéphanie

AU - Carling, David

AU - Aubert, Sébastien

AU - Vindrieux, David

AU - Bernard, David

PY - 2013

Y1 - 2013

N2 - Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway.

AB - Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway.

KW - Animals

KW - Breast Neoplasms

KW - Cell Aging

KW - Cell Growth Processes

KW - Cell Line

KW - Cell Membrane

KW - Cell Transformation, Neoplastic

KW - Cyclic AMP-Dependent Protein Kinases

KW - Cytoplasm

KW - Down-Regulation

KW - Humans

KW - Kv1.1 Potassium Channel

KW - Mammary Glands, Human

KW - Membrane Potentials

KW - Mice

KW - NIH 3T3 Cells

KW - Phosphorylation

KW - Signal Transduction

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/0008-5472.CAN-12-3690

DO - 10.1158/0008-5472.CAN-12-3690

M3 - Article

C2 - 23774215

VL - 73

SP - 5253

EP - 5265

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 16

ER -